Novel alkynyl derivatives as modulators of metabotropic glutamate receptors

ABSTRACT

The present invention relates to novel compounds of formula I wherein W, n, X and W′ are defined in the description; invention compounds are modulators of metabotropic glutamate receptors—subtype 5 (“mGluR5”) which are useful for the treatment of central nervous system disorders as well as other disorders modulated by mGluR5 receptors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/332,364, filed Dec. 20, 2011, pending, which is a continuation ofU.S. patent application Ser. No. 11/630,013, filed Dec. 18, 2006, nowU.S. Pat. No. 8,101,637, which is the national stage application under35 U.S.C. §371 of PCT Patent Application No. PCT/IB2005/002390, filedJun. 17, 2005, which claims priority to UK Patent Application No. GB0413605.7, filed Jun. 17, 2004. The contents of each of the foregoingapplications are incorporated herein by reference in their entirety.

SUMMARY OF THE INVENTION

The present invention provides new compounds of formula I, wherein W, n,X and W′ are defined as in formula I; invention compounds are modulatorsof metabotropic glutamate receptors—subtype 5 (“mGluR5”) which areuseful for the treatment of central nervous system disorders as well asother disorders modulated by mGluR5 receptors.

BACKGROUND OF THE INVENTION

Glutamate, the major amino-acid transmitter in the mammalian centralnervous system (CNS), mediates excitatory synaptic neurotransmissionthrough the activation of ionotropic glutamate receptorsreceptor-channels (iGluRs, namely NMDA, AMPA and kainate) andmetabotropic glutamate receptors (mGluRs). iGluRs are responsible forfast excitatory transmission (Nakanishi S. et al., (1998) Brain Res.Rev., 26:230-235) while mGluRs have a more modulatory role thatcontributes to the fine-tuning of synaptic efficacy. Glutamate isassociated with numerous physiological functions such as long-termpotentiation (LTP), a process believed to underlie learning and memorybut also cardiovascular regulation, sensory perception, and thedevelopment of synaptic plasticity. In addition, glutamate plays animportant role in the patho-physiology of different neurological andpsychiatric diseases, especially when an imbalance in glutamatergicneurotransmission occurs.

The mGluRs are seven-transmembrane G protein-coupled receptors. Theeight members of the family are classified into three groups (Groups I,II & III) according to their sequence homology and pharmacologicalproperties (Schoepp D. D. et al. (1999) Neuropharmacology,38:1431-1476). Activation of mGluRs leads to a large variety ofintracellular responses and activation of different transductionalcascades. Among mGluR members, the mGluR5 subtype is of high interestfor counterbalancing the deficit or excesses of neurotransmission inneuropsychatric diseases. mGluR5 belongs to Group I and its activationinitiates cellular responses through G-protein mediated mechanisms.mGluR5 is coupled to phospholipase C and stimulates phosphoinositidehydrolysis and intracellular calcium mobilization.

mGluR5 proteins have been demonstrated to be localized in post-synapticelements adjacent to the post-synaptic density (Lujan R. et al. (1996)Eur. J. Neurosci. 8:1488-500; Lujan R. et al. (1997) J. Chem.Neuroanat., 13:219-41) and are also detected in the pre-synapticelements (Romano C. et al. (1995) J. Comp. Neurol. 355:455-69). MGluR5receptors can therefore modify the post-synaptic responses toneurotransmitter or regulate neurotransmitter release.

In the CNS, mGluR5 receptors are abundant mainly throughout cortex,hippocampus, caudate-putamen and nucleus accumbens. As these brain areashave been shown to be involved in emotion, motivational processes and innumerous aspects of cognitive function, mGluR5 modulators are predictedto be of therapeutic interest.

A variety of clinical indications have been suggested to be targets forthe development of subtype selective mGluR modulators. These includeepilepsy, neuropathic and inflammatory pain, numerous psychiatricdisorders (eg anxiety and schizophrenia), movement disorders (egParkinson disease), neuroprotection (stroke and head injury), migraineand addiction/drug dependency (for reviews, see Brauner-Osborne H. etal. (2000) J. Med. Chem. 43:2609-45; Bordi F. and Ugolini A. (1999)Prog. Neurobiol. 59:55-79; Spooren W. et al. (2003) Behay. Pharmacol.14:257-77).

mGluR5 receptor is considered as a potential drug target for thetreatment of psychiatric and neurological disorders Anxiety Disorders,Attentional disorders, Eating Disorders, Mood Disorders, PsychoticDisorders, Cognitive Disorders, Personality Disorders and Substance ofAbuse related disorders

Other research supports a role of mGluR5 modulation in the treatment ofFragile X syndrome (Laura N. Antar et al. The Journal of Neuroscience,Mar. 17, 2004, 24-11, 2648-2655, Weiler I. J., Proc. Natl. Acad. Sci.USA, 1997, 94, 5395-5400), Obesity and Gastro-Esophageal Reflux Disease(Blackshaw L. A. et al., presentation at the conferenceNeurogastroentorology & Morality, Madison, Wis., 14 Nov. 2001).

International Patent Publications WO03/104206, GB2124227, WO03/050087and WO03/013247 describe 3-phenoxyprop-1-ynyl and3-pyridinoxyprop-1-ynyl, having herbicidal properties. In US6166060,4-(5-phenylpent-1-ynyl)-1H-imidazole is described as an H₃ histamineantagonist.

International patent publications WO99/02497, WO01/16121 and WO02/46166describe heteroaryl ethynyl compounds and their use as metabotropicglutamate receptor antagonists. International patent publicationsWO2005/044265, WO2005/044266 and WO2005/044267 disclose a class of3-(pyridin-2-yl)prop-2-ynyl derivatives as being useful in GERDindication.

Compounds of general formula I can show potent activity and selectivityon mGluR5 receptor. The compounds of the invention can demonstrateadvantageous properties over compounds of the prior art. Improvementshave been observed in one or more of the following characteristics ofthe compounds of the invention: the potency on the target, theselectivity for the target, the solubility, the bioavailability, thebrain penetration, and the activity in behavioural models of psychiatricand neurological disorders.

The present invention relates to a method of treating or preventing acondition in a mammal, including a human, the treatment or prevention ofwhich is affected or facilitated by the neuromodulatory effect of mGluR5modulators.

FIGURES

FIG. 1 shows that the representative Example 256 of the inventionsignificantly attenuates marble burying in mice at doses of 30 mg/kg po.

FIG. 2 shows that the representative Example 255 of the inventionsignificantly attenuates marble burying in mice at doses of 50 mg/kg po.

FIG. 3 shows that the representative Example 256 of the inventionsignificantly increases punished drinking in rats at doses of 10 mg/kgpo.

FIG. 4 shows that the representative Example 130 of the inventionsignificantly increases punished drinking in rats at doses of 30 mg/kgpo.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, there are provided new compounds ofthe general formula I

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein:

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from the group consisting of C, N, O and S; provided that W is a    heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   n is an integer from 1 to 6;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₁-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁹, C₀-C₆—NR⁹S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹, C₀-C₆-alkyl-NR⁹C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁹—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹—C(═O)—NR¹⁰, C₀-C₆-alkyl-NR⁹—C(═NR¹⁰NR¹¹,    C₀-C₆-alkyl-(C═NR⁹)NR¹⁰, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁹) or    C₀-C₆-alkyl-O—N═CR⁹ substituents;    -   R⁹, R¹⁰ and R¹¹ are each independently selected from hydrogen,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, heterocycle;

-   W′ denotes a 5- or 6-membered ring containing one or more atoms    independently selected from C, N, O and S, which ring may optionally    be fused with a 5- or 6-membered ring containing one or more atoms    independently selected from C, N, O and S, provided that W′ is a    aryl, heteroaryl or heterocycle selected from the group of formula:

-   -   G^(q) groups are each independently selected from the group        consisting of hydrogen, halogen, CN, OH, nitro, an optionally        substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,        C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹²,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR¹², C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O-heteroaryl, heteroaryl, C₁-C₆-alkyl-heteroaryl, aryl, O-aryl,        C₁-C₆-alkylaryl, C₁-C₆-alkylhalo-OR¹², C₃-C₆-alkynyl-OR¹²,        C₃-C₆-alkenyl-OR¹², C₀-C₆-alkyl-S—R¹², O—C₂-C₆-alkyl-S—R¹²,        C₀-C₆-alkyl-S(═O)—R¹², O—C₂-C₆-alkyl-S(═O)—R¹²,        C₀-C₆-alkyl-S(═O)₂—R¹², O—C₁-C₆-alkyl-S(═O)₂—R¹²,        C₀-C₆-alkyl-NR¹²R¹³, O—C₂-C₆-alkyl-NR¹²R¹³,        C₀-C₆-alkyl-S(═O)₂NR¹²R¹³, C₀-C₆-alkyl-NR¹²—S(═O)₂R¹³,        O—C₁-C₆-alkyl-S(═O)₂NR¹²R¹³, O—C₂-C₆-alkyl-NR¹²—S(═O)₂R¹³,        C₀-C₆-alkyl-C(═O)—NR¹²R¹³, C₀-C₆-alkyl-NR¹²C(═O)—R¹³,        O—C₁-C₆-alkyl-C(═O)—NR¹²R¹³, O—C₂-C₆-alkyl-NR¹²C(═O)—R¹³,        C₀-C₆-alkyl-OC(═O)—R¹², C₀-C₆-alkyl-C(═O)—OR¹²,        O—C₂-C₆-alkyl-OC(═O)—R¹², O—C₁-C₆-alkyl-C(═O)—OR¹²,        C₀-C₆-alkyl-C(═O)—R¹², O—C₁-C₆-alkyl-C(═O)—R¹²,        C₀-C₆-alkyl-NR¹²—C(═O)—OR¹³, C₀-C₆-alkyl-O—C(═O)—NR¹²R¹³ or        C₀-C₆-alkyl-NR¹²—C(═O)—NR¹³R¹⁴ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   q is an integer from 1 to 5;    -   R¹², R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z⁹, Z¹⁰, Z¹¹, Z¹², Z¹³, Z¹⁴, Z¹⁵, Z¹⁶ and Z¹⁷ are each        independently selected from the group consisting of —C═, —C═C—,        —C(═O)—, —C(═S)—, —C—, —O—, —N═, —N— or —S— which may further be        substituted by 1 to 5 G^(q) groups;    -   B¹, B² and B³ are each selected independently from C, C═C, C═N,        S, O or N which may further be substituted by one G^(q) group;    -   Any N may be an N-oxide;        provided that:    -   when X is independently selected from NR¹⁵, O, S or an        optionally substituted C₁-C₆-alkyl, n is 1, W is an optionally        substituted 2-pyridinyl and R¹⁵ is independently selected from        hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl, C₁-C₆-alkyl-heteroaryl        or aryl, W′ can not be an optionally substituted aryl;    -   when X is O, n is 1 and W′ is an optionally substituted aryl or        heteroaryl, W can not be an optionally substituted 3-pyridazinyl        or 4-pyrimidinyl;    -   when X is CH₂, n is 1 and W′ is aryl, W can not be        2-phenyloxazol-4-yl, 4-phenyloxazol-2-yl,        4-(3-(benzyloxy)propyl)-oxazol-2-yl, 4-phenylthiazol-2-yl,        4-methylthiazol-2-yl or benzo[d]oxazol-2-yl,        benzo[d]thiazol-2-yl;    -   when X is O, n is 1 and W is an optionally substituted        pyridinyl, W′ can not be an optionally substituted 2-pyridinyl;    -   when X is CH₂, n is 2 and W′ is aryl, W can not be 4-imidazolyl.    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

DEFINITION OF TERMS

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

For the avoidance of the doubt it is to be understood that in thisspecification “C₁-C₆” means a carbon group having 1, 2, 3, 4, 5 or 6carbons atoms. “C₀-C₆” means a carbon group having 0, 1, 2, 3, 4, 5 or 6carbon atoms.

In this specification “C” means a carbon atom.

In the case where a subscript is the integer 0 (zero) the group to whichthe subscript refers to indicates that the group is absent, i.e. thereis a direct bond between the groups.

In this specification, unless stated otherwise, the term “bond” is asaturated bond.

In the above definition, the term “C₁-C₆-alkyl” includes both straightand branched chain alkyl groups and may be groups such as methyl, ethyl,n-propyl, i-propyl n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl,i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl, t-hexyl or the like.

In this specification, unless stated otherwise, the term “alkenyl”includes both straight and branched chain alkenyl groups. The term“C₂-C₆-alkenyl” refers to an alkenyl group having 2 to 6 carbon atomsand one or two double bonds, and may be, but is not limited to vinyl,allyl, 1-propenyl, i-propenyl, 1-butenyl, i-butenyl, crotyl, pentenyl,i-pentenyl, hexenyl and the like.

In this specification, unless stated otherwise, the term “alkynyl”includes both straight and branched chain alkynyl groups. The termC₂-C₆-alkynyl having 2 to 6 carbon atoms and one or two triple bonds,and may be, but is not limited to ethynyl, propargyl, butynyl, ibutynyl,pentynyl, i-pentynyl, hexynyl and the like.

The term “aryl” refers to an optionally substituted monocyclic orbicyclic hydrocarbon ring system containing at least one unsaturatedaromatic ring. Examples and suitable values of the term “aryl” arephenyl, naphthyl, 1,2,3,4,-tetrahydronaphthyl, indyl, indenyl and thelike.

In this specification, unless stated otherwise, the term “halo” or“halogen” may be fluoro, chloro, bromo or iodo.

In this specification, unless stated otherwise, a 5- or 6-membered ringcontaining one or more atoms independently selected from C, N, O, or S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Example ofsuch rings may be, but are not limited to furyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl,triazolyl, morpholinyl, piperazinyl, piperidinyl, piperidonyl,pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,thiomorpholinyl, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl and thelike.

In this specification, unless stated otherwise, the term “alkylaryl”,“alkylheteroaryl” and “alkylcycloalkyl” refer to a substituent that isattached via the alkyl group to an aryl, heteroaryl and cycloalkylgroup. The term “C₁-C₆-alkylaryl” includes aryl-C₁-C₆-alkyl group suchas benzyl group, 1-phenylethyl group, 2-phenylethyl group,1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group,1-naphthylmethyl group, 2-naphthylmethyl group or the like. The term“C₁-C₆-alkyheteroaryl” includes heteroaryl-C₁-C₃-alkyl group, whereinexamples of heteroaryl are the same as those illustrated in the abovedefinition, such as 2-furylmethyl group, 3-furylmethyl group,2-thienylmethyl group, 3-thienylmethyl group, 1-imidazolylmethyl group,2-imidazolylmethyl group, 2-thiazolylmethyl group, 2-pyridylmethylgroup, 3-pyridylmethyl group, 1-quinolylmethyl group or the like.

In this specification, unless stated otherwise, the term “alkylhalo”means an alkyl group as defined above, substituted with one or morehalogen. The term “C₁-C₆-alkylhalo” may include, but not limited tofluoroethyl, difluoromethyl, trifluoromethyl, fluoroethyl,difluoroethyl, bromoethyl and the like. The term “O—C₁-C₆-alkylhalo” mayinclude, but is not limited to fluoromethoxy, difluoromethoxy,trifluoromethoxy, fluoroethoxy and the like.

In the specification, unless stated otherwise, the term “heteroaryl”refers to an optionally substituted monocyclic or bicyclic unsaturated,aromatic ring system containing at least on heteroatom selectedindependently from O, N or S to form a ring such as furyl (furan ring),benzofuranyl (benzofuran), thienyl (thiophene), benzothiophenyl(benzothiophene), oxadiazolyl (oxadiazole ring), pyrrolyl (pyrrolering), imidazolyl (imidazole ring), pyrazolyl (pyrazole ring), thiazolyl(thiazole ring), isothiazolyl (isothiazole ring), triazolyl (triazolering), tetrazolyl (tetrazole ring), pyridil (pyridine ring), pyrazynyl(pyrazine ring), pyrimidinyl (pyrimidine ring), pyridazinyl (pyridazinering), indolyl (indole ring), isoindolyl (isoindole ring),benzoimidazolyl (benzimidazole ring), purinyl group (purine ring),quinolyl (quinoline ring), phtalazinyl (phtalazine ring), naphtyridinyl(naphtyridine ring), quinoxalinyl (quinoxaline ring), cinnolyl(cinnoline ring), pteridinyl (pteridine ring), oxazolyl (oxazole ring),isoxazolyl (isoxazole ring), benzoxazolyl (benzoxazole ring),benzothiazolyl (benzothiaziole ring), furazanyl (furazan ring),benzotriazolyl (benzotriazol ring), imidazopyridinyl (imidazopyridinering), pyrazolopyridinyl (pyrazolopyridine ring), and the like.

In this specification, unless stated otherwise, the term “heterocycle”refers to an optionally substituted, mono cyclic or bicyclic saturated,partially saturated or unsaturated ring system containing at least oneheteroatom selected independently from N, O or S.

In this specification, unless stated otherwise, the term “cycloalkyl”refers to an optionally substituted carbocycles containing noheteroatoms, includes mono-, bi-, and tricyclic saturated carbocycles,as well as fused ring systems. Such fused ring systems can include onring that is partially or fully unsaturated such as a benzene ring toform fused ring systems such as benzo fused carbocycles. Cycloalkylincludes such fused ring systems as spirofused ring systems. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,decahydronaphthalene, adamantane, indanyl, fluorenyl,1,2,3,4-tetrahydronaphthalene and the like. The term “(C₃-C₇)cycloalkyl”may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andthe like.

“Solvate” refers to a complex of variable stoichiometry formed by asolute (e.g. a compound of formula I) and a solvent. The solvent is apharmaceutically acceptable solvent as water preferably; such solventmay not interfere with the biological activity of the solute.

In this specification, unless stated otherwise, the term “optionallysubstituted” refers to radicals further bearing one or more substituentswhich may be, but are not limited to, hydroxyl, alkoxy, mercapto, aryl,heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano,cyanomethyl, nitro, amino, amido, amidine, carboxyl, carboxamide,carbamate, ester, sulfonyl, sulfonamide, and the like.

Preferred compounds of the present invention are compounds of formula IIdepicted below

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from a group consisting of C, N, O and S; provided that W is a    heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₁-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁹, C₀-C₆—NR⁹S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹, C₀-C₆-alkyl-NR⁹C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁹—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹—C(═O)—NR¹⁰, C₀-C₆-alkyl-NR⁹—C(═NR¹⁰NR¹¹,    C₀-C₆-alkyl-(C═NR⁹)NR¹⁰, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁹) or    C₀-C₆-alkyl-O—N═CR⁹ substituents;    -   R⁹, R¹⁰ and R¹¹ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, heterocycle;

-   W′ denotes a 5- or 6-membered ring containing one or more atoms    independently selected from C, N, O and S, which ring may optionally    be fused with a 5- or 6-membered ring containing one or more atoms    independently selected from C, N, O and S, provided that W′ is a    aryl, heteroaryl or heterocycle selected from the group of formula:

G^(q) groups are each independently selected from the group consistingof hydrogen, halogen, CN, OH, nitro, an optionally substitutedC₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl,O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,O—C₂-C₆-alkyl-OR¹², O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl,O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹², C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl,O-heteroaryl, heteroaryl, C₁-C₆-alkyl-heteroaryl, aryl, O-aryl,C₁-C₆-alkylaryl, C₁-C₆-alkylhalo-OR¹², C₃-C₆-alkynyl-OR¹²,C₃-C₆-alkenyl-OR¹², C₀-C₆-alkyl-S—R¹², O—C₂-C₆-alkyl-S—R¹²,C₀-C₆-alkyl-S(═O)—R¹², O—C₂-C₆-alkyl-S(═O)—R¹², C₀-C₆-alkyl-S(═O)₂—R¹²,O—C₁-C₆-alkyl-S(═O)₂—R¹², C₀-C₆-alkyl-NR¹²R¹³, O—C₂-C₆-alkyl-NR¹²R¹³,C₀-C₆-alkyl-S(═O)₂NR¹²R¹³, C₀-C₆-alkyl-NR¹²—S(═O)₂R¹³,O—C₁-C₆-alkyl-S(═O)₂NR¹²R¹³, O—C₂-C₆-alkyl-NR¹²—S(═O)₂R¹³,C₀-C₆-alkyl-C(═O)—NR¹²R¹³, C₀-C₆-alkyl-NR¹²C(═O)—R¹³,O—C₁-C₆-alkyl-C(═O)—NR¹²R¹³, O—C₂-C₆-alkyl-NR¹²C(O) K¹³,C₀-C₆-alkyl-OC(═O)—R′², C₀-C₆-alkyl-C(═O)—OR¹²,O—C₂-C₆-alkyl-OC(═O)—R¹², O—C₁-C₆-alkyl-C(═O)—OR¹²,C₀-C₆-alkyl-C(═O)—R¹², O—C₁-C₆-alkyl-C(═O)—R¹²,C₀-C₆-alkyl-NR¹²—C(═O)—OR¹³, C₀-C₆-alkyl-O—C(═O)—NR¹²R¹³ orC₀-C₆-alkyl-NR¹²—C(═O)—NR¹³R¹⁴ substituents; wherein optionally twosubstituents are combined to the intervening atoms to form a bicyclicaryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ringis optionally further substituted with 1-5 independent hydrogen,halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₃-C₇-cycloalkyl,O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl,O-heteroaryl, heteroaryl, C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;

-   -   q is an integer from 1 to 5;    -   R¹², R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z⁹, Z¹⁰, Z¹¹, Z¹², Z¹³, Z¹⁴, Z¹⁵, Z¹⁶ and R¹⁷ are each        independently selected from the group consisting of —C═, —C═C—,        —C(═O)—, —C(═S)—, —C—, —O—, —N═, —N— or —S-which may further be        substituted by 1 to 5 G^(q) groups;    -   B¹, B² and B³ are each selected independently from the group        consisting of C, C═C, C═N, S, O or N which may further be        substituted by one G^(q) group;    -   Any N may be an N-oxide;        provided that:    -   when X is independently selected from NR¹⁵, O, S or an        optionally substituted C₁-C₆-alkyl, W is an optionally        substituted 2-pyridinyl and R¹⁵ is independently selected from        hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl, C₁-C₆-alkyl-heteroaryl        or aryl, W′ can not be an optionally substituted aryl;    -   when X is O and W′ is an optionally substituted aryl or        heteroaryl, W can not be an optionally substituted 3-pyridazinyl        or 4-pyrimidinyl;    -   when X is CH₂ and W′ is aryl, W can not be 2-phenyloxazol-4-yl,        4-phenyloxazol-2-yl, 4-(3-(benzyloxy)propyl)-oxazol-2-yl,        4-phenylthiazol-2-yl, 4-methylthiazol-2-yl or        benzo[d]oxazol-2-yl, benzo[d]thiazol-2-yl;    -   when X is O and W is an optionally substituted pyridinyl, W′ can        not be an optionally substituted 2-pyridinyl;    -   when X is CH₂CH₂ and W′ is aryl, W can not be 4-imidazolyl.    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

More preferred compounds of the present invention are compounds offormula II-A depicted below

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from the group consisting of C, N, O and S; provided that W is a    heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₁-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁹, C₀-C₆—NR⁹S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹, C₀-C₆-alkyl-NR⁹C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁹—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹—C(═O)—NR¹⁰, C₀-C₆-alkyl-NR⁹—C(═NR¹⁰NR¹¹,    C₀-C₆-alkyl-(C═NR⁹)NR¹⁰, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁹) or    C₀-C₆-alkyl-O—N═CR⁹ substituents;    -   R⁹, R¹⁰ and R¹¹ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, heterocycle;

-   Z⁹, Z¹⁰, Z¹¹, Z¹², Z¹³, Z¹⁴, Z¹⁵, Z¹⁶ and Z¹⁷ are each independently    selected from the group consisting of —C═, —C═C—, —C(═O)—, —C(═S)—,    —C—, —O—, —N═, —N— or —S— which may further be substituted by 1 to 5    G^(q) groups;

-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹², O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹²,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹², C₃-C₆-alkynyl-OR¹², C₃-C₆-alkenyl-OR¹²,    C₀-C₆-alkyl-S—R¹², O—C₂-C₆-alkyl-S—R¹², C₀-C₆-alkyl-S(═O)—R¹²,    O—C₂-C₆-alkyl-S(═O)—R¹², C₀-C₆-alkyl-S(═O)₂—R¹²,    O—C₁-C₆-alkyl-S(═O)₂—R¹², C₀-C₆-alkyl-NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²R¹³, C₀-C₆-alkyl-S(═O)₂NR¹²R¹³,    C₀-C₆-alkyl-NR¹²—S(═O)₂R¹³, O—C₁-C₆-alkyl-S(═O)₂NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²—S(═O)₂R¹³, C₀-C₆-alkyl-C(═O)—NR¹²R¹³,    C₀-C₆-alkyl-NR¹²C(═O)—R¹³, O—C₁-C₆-alkyl-C(═O)—NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²C(═O)—R¹³, C₀-C₆-alkyl-OC(═O)—R¹²,    C₀-C₆-alkyl-C(═O)—OR¹², O—C₂-C₆-alkyl-OC(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—OR¹², C₀-C₆-alkyl-C(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—R¹², C₀-C₆-alkyl-NR¹²—C(═O)—OR¹³,    C₀-C₆-alkyl-O—C(═O)—NR¹²R¹³ or C₀-C₆-alkyl-NR¹²—C(═O)—NR¹³R¹⁴    substituents; wherein optionally two substituents are combined to    the intervening atoms to form a bicyclic aryl, cycloalkyl,    heterocycloalkyl or heteroaryl ring; wherein each ring is optionally    further substituted with 1-5 independent hydrogen, halogen, CN, OH,    nitro, an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,    C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,    O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O-heteroaryl, heteroaryl, C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;

-   q is an integer from 1 to 5;    -   R¹², R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In one aspect, the compounds of the present invention are represented byFormula II-A wherein the heterocyclic ring system is specified as in theformula II-A1 depicted below

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from the group consisting of C, N, O and S; provided that W is a    heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₁-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁹, C₀-C₆—NR⁹S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹, C₀-C₆-alkyl-NR⁹C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁹—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹—C(═O)—NR¹⁰)C₀-C₆-alkyl-NR⁹—C(═NR¹⁰NR¹¹,    C₀-C₆-alkyl-(C═NR⁹)NR¹⁰, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁹) or    C₀-C₆-alkyl-O—N═CR⁹ substituents;    -   R⁹, R¹⁰ and R¹¹ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, heterocycle;

-   B¹ and B² are each selected independently from N or C which may    further be substituted by G^(q) groups;

-   B³ is selected independently from C, C═C, C═N, S, O or N which may    further be substituted by G^(q) groups;

-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹², O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹²,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹², C₃-C₆-alkynyl-OR¹², C₃-C₆-alkenyl-OR¹²,    C₀-C₆-alkyl-S—R¹², O—C₂-C₆-alkyl-S—R¹², C₀-C₆-alkyl-S(═O)—R¹²,    O—C₂-C₆-alkyl-S(═O)—R¹², C₀-C₆-alkyl-S(═O)₂—R¹²,    O—C₁-C₆-alkyl-S(═O)₂—R¹², C₀-C₆-alkyl-NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²R¹³, C₀-C₆-alkyl-S(═O)₂NR¹²R¹³,    C₀-C₆-alkyl-NR¹²—S(═O)₂R¹³, O—C₁-C₆-alkyl-S(═O)₂NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²—S(═O)₂R¹³, C₀-C₆-alkyl-C(═O)—NR¹²R¹³,    C₀-C₆-alkyl-NR¹²C(═O)—R¹³, O—C₁-C₆-alkyl-C(═O)—NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²C(═O)—R¹³, C₀-C₆-alkyl-OC(═O)—R′²,    C₀-C₆-alkyl-C(═O)—OR¹², O—C₂-C₆-alkyl-OC(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—OR¹², C₀-C₆-alkyl-C(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—R¹², C₀-C₆-alkyl-NR¹²—C(═O)—OR¹³,    C₀-C₆-alkyl-O—C(═O)—NR¹²R¹³ or C₀-C₆-alkyl-NR¹²—C(═O)—NR¹³R¹⁴    substituents;

-   q is an integer from 1 to 5;    -   R¹², R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In a second aspect, the compounds of the present invention arerepresented by Formula II-A wherein the heterocyclic ring system isspecified as in the formula II-A2 depicted below

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from the group consisting of C, N, O and S; provided that W is a    heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₁-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁹, C₀-C₆—NR⁹S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹, C₀-C₆-alkyl-NR⁹C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁹—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹—C(═O)—NR¹⁰, C₀-C₆-alkyl-NR⁹—C(═NR¹⁰NR¹¹,    C₀-C₆-alkyl-(C═NR⁹)NR¹⁰, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁹) or    C₀-C₆-alkyl-O—N═CR⁹ substituents;    -   R⁹, R¹⁰ and R¹¹ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, heterocycle;

-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹², O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹²,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹², C₃-C₆-alkynyl-OR¹², C₃-C₆-alkenyl-OR¹²,    C₀-C₆-alkyl-S—R¹², O—C₂-C₆-alkyl-S—R¹², C₀-C₆-alkyl-S(═O)—R¹²,    O—C₂-C₆-alkyl-S(═O)—R¹², C₀-C₆-alkyl-S(═O)₂—R¹²,    O—C₁-C₆-alkyl-S(═O)₂—R¹², C₀-C₆-alkyl-NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²R¹³, C₀-C₆-alkyl-S(═O)₂NR¹²R¹³,    C₀-C₆-alkyl-NR¹²—S(═O)₂R¹³, O—C₁-C₆-alkyl-S(═O)₂NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²—S(═O)₂R¹³, C₀-C₆-alkyl-C(═O)—NR¹²R¹³,    C₀-C₆-alkyl-NR¹²C(═O)—R¹³, O—C₁-C₆-alkyl-C(═O)—NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²C(═O)—R¹³, C₀-C₆-alkyl-OC(═O)—R¹²,    C₀-C₆-alkyl-C(═O)—OR¹², O—C₂-C₆-alkyl-OC(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—OR¹², C₀-C₆-alkyl-C(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—R¹², C₀-C₆-alkyl-NR¹²—C(═O)—OR¹³,    C₀-C₆-alkyl-O—C(═O)—NR¹²R¹³ or C₀-C₆-alkyl-NR¹²—C(═O)—NR¹³R¹⁴    substituents;

-   q is an integer from 1 to 5;    -   R¹², R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In a more preferred aspect of Formula II-A2, the compounds of theinvention are represented by Formula II-A2-a

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   R¹, R², R³ and R⁴ are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁵, O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR⁵,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR⁵, C₃-C₆-alkynyl-OR⁵, C₃-C₆-alkenyl-OR⁵,    C₀-C₆-alkyl-S—R⁵, O—C₂-C₆-alkyl-S—R⁵, C₀-C₆-alkyl-S(═O)—R⁵,    O—C₂-C₆-alkyl-S(═O)—R⁵, C₀-C₆-alkyl-S(═O)₂—R⁵,    O—C₁-C₆-alkyl-S(═O)₂—R⁵, C₀-C₆-alkyl-NR⁵R⁶, O—C₂-C₆-alkyl-NR⁵R⁶,    C₀-C₆-alkyl-S(═O)₂NR⁵R⁶, C₀-C₆-alkyl-NR⁵—S(═O)₂R⁶,    O—C₁-C₆-alkyl-S(═O)₂NR⁵R⁶, O—C₂-C₆-alkyl-NR⁵—S(═O)₂R⁶,    C₀-C₆-alkyl-C(═O)—NR⁵R⁶, C₀-C₆-alkyl-NR⁵C(═O)—R⁶,    O—C₁-C₆-alkyl-C(═O)—NR⁵R⁶, O—C₂-C₆-alkyl-NR⁵C(═O)—R⁶,    C₀-C₆-alkyl-OC(═O)—R⁵, C₀-C₆-alkyl-C(═O)—OR⁵,    O—C₂-C₆-alkyl-OC(═O)—R⁵, O—C₁-C₆-alkyl-C(═O)—OR⁵,    C₀-C₆-alkyl-C(═O)—R⁵, O—C₁-C₆-alkyl-C(═O)—R⁵,    C₀-C₆-alkyl-NR⁵—C(═O)—OR⁶, C₀-C₆-alkyl-O—C(═O)—NR⁵R⁶ or    C₀-C₆-alkyl-NR⁵—C(═O)—NR⁶R⁷ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁵, R⁶ and R⁷ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₁-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁸, C₀-C₆—NR⁸S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁸, C₀-C₆-alkyl-C(═O)—NR⁸, C₀-C₆-alkyl-NR⁸C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁸—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁸,    C₀-C₆-alkyl-NR⁸—C(═O)—NR⁹, C₀-C₆-alkyl-NR⁸—C(═NR⁹)NR¹⁰,    C₀-C₆-alkyl-(C═NR⁸)NR⁹, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁸—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁸) or    C₀-C₆-alkyl-O—N═CR⁸ substituents;    -   R⁸, R⁹ and R¹⁰ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹¹, O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹¹,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹¹, C₃-C₆-alkynyl-OR¹¹, C₃-C₆-alkenyl-OR¹¹,    C₀-C₆-alkyl-S—R¹¹, O—C₂-C₆-alkyl-S—R¹¹, C₀-C₆-alkyl-S(═O)—R¹¹,    O—C₂-C₆-alkyl-S(═O)—R¹¹, C₀-C₆-alkyl-S(═O)₂—R¹¹,    O—C₁-C₆-alkyl-S(═O)₂—R¹¹, C₀-C₆-alkyl-NR¹¹R¹²,    O—C₂-C₆-alkyl-NR¹¹R¹², C₀-C₆-alkyl-S(═O)₂NR¹¹R¹²,    C₀-C₆-alkyl-NR¹¹—S(═O)₂R¹², O—C₁-C₆-alkyl-S(═O)₂NR¹¹R¹²,    O—C₂-C₆-alkyl-NR¹¹—S(═O)₂R¹², C₀-C₆-alkyl-C(═O)—NR¹¹R¹²,    C₀-C₆-alkyl-NR¹¹C(═O)—R¹², O—C₁-C₆-alkyl-C(═O)—NR¹¹R¹²,    O—C₂-C₆-alkyl-NR¹¹C(═O)—R¹², C₀-C₆-alkyl-OC(═O)—R¹¹,    C₀-C₆-alkyl-C(═O)—OR¹¹, O—C₂-C₆-alkyl-OC(═O)—R¹¹,    O—C₁-C₆-alkyl-C(═O)—OR¹¹, C₀-C₆-alkyl-C(═O)—R¹¹,    O—C₁-C₆-alkyl-C(═O)—R¹¹, C₀-C₆-alkyl-NR¹¹—C(═O)—OR¹²,    C₀-C₆-alkyl-O—C(═O)—NR¹¹R¹² or C₀-C₆-alkyl-NR¹¹—C(═O)—NR¹²R¹³    substituents;-   q is an integer from 1 to 5;    -   R¹¹, R¹² and R¹³ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In a more preferred aspect of Formula II-A2-a, the compounds of theinvention are represented by Formula II-A2-a1

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   R¹, R², R³ and R⁴ are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, an optionally substituted    C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₀-C₆-alkyl-NR⁵R⁶,    C₀-C₆-alkyl-S(═O)₂NR⁵R⁶, C₀-C₆-alkyl-NR^(S)—S(═O)₂R⁶,    C₀-C₆-alkyl-C(═O)—NR⁵R⁶, C₀-C₆-alkyl-NR⁵C(═O)—R⁶,    C₀-C₆-alkyl-OC(═O)—R⁵, C₀-C₆-alkyl-C(═O)—OR⁵, C₀-C₆-alkyl-C(═O)—R⁵    or C₀-C₆-alkyl-NR⁵—C(═O)—NR⁶R⁷ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁵, R⁶ and R⁷ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        heteroaryl, C₁-C₆-alkyl-hetero aryl, aryl;-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, O—C₀-C₆-alkyl, C₀-C₆-alkyl-O, S—C₀-C₆-alkyl,    C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O), C₀-C₆-alkyl-S(═O)₂,    C₀-C₆-alkyl-NR⁸, C₀-C₆—NR⁸S(═O)₂, C₀-C₆-alkyl-S(═O)₂NR⁸,    C₀-C₆-alkyl-C(═O)—NR⁸, C₀-C₆-alkyl-NR⁸C(═O),    C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═O)—NR⁸—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O) or C₀-C₆-alkyl-NR⁸—C(═O)—NR⁹ substituents;    -   R⁸ and R⁹ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, O—C₁-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₂-C₆-alkyl-OR¹⁰, O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹⁰,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹⁰, C₀-C₆-alkyl-S(═O)—R¹⁰,    O—C₂-C₆-alkyl-S(═O)—R¹⁰, C₀-C₆-alkyl-S(═O)₂—R¹⁰,    O—C₁-C₆-alkyl-S(═O)₂—R¹⁰, C₀-C₆-alkyl-NR¹⁰R¹¹,    O—C₂-C₆-alkyl-NR¹⁰R¹¹, C₀-C₆-alkyl-S(═O)₂NR¹⁰R¹¹,    C₀-C₆-alkyl-NR¹⁰—S(═O)₂R¹¹, O—C₁-C₆-alkyl-S(═O)₂NR¹⁰R¹¹,    O—C₂-C₆-alkyl-NR¹⁰—S(═O)₂R¹¹, C₀-C₆-alkyl-C(═O)—NR¹⁰R¹¹,    C₀-C₆-alkyl-NR¹⁰C(═O)—R¹¹, O—C₁-C₆-alkyl-C(═O)—NR¹⁰R¹¹,    O—C₂-C₆-alkyl-NR¹⁰C(═O)—R¹¹, C₀-C₆-alkyl-C(═O)—R¹⁰,    O—C₁-C₆-alkyl-C(═O)—R¹⁰ or C₀-C₆-alkyl-NR¹⁰—C(═O)—NR¹¹R¹²    substituents;-   q is an integer from 1 to 5;    -   R¹⁰, R¹¹ and R¹² are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In a more preferred aspect, the compounds of the present invention arerepresented by Formula II-A2-a1 wherein the linker is specified as inthe formula II-A2-a2 depicted below

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   R¹, R², R³ and R⁴ are each independently selected from the group    consisting of hydrogen, halogen, an optionally substituted    C₁-C₆-alkyl, C₁-C₆-alkylhalo or C₀-C₆-alkyl-NR⁵R⁶ substituents;    -   R⁵ and R⁶ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        heteroaryl, C₁-C₆-alkyl-heteroaryl, aryl;-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, an optionally substituted    C₁-C₆-alkyl, C₁-C₆-alkylhalo, O—C₀-C₆-alkyl, O—C₀-C₆-alkylaryl,    heteroaryl or aryl;-   q is an integer from 1 to 5;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In a third aspect, the compounds of the present invention arerepresented by Formula II-A wherein the heterocyclic ring system isspecified as in the formula II-A3 depicted below

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from the group consisting of C, N, O and S; provided that W is a    heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected the        group consisting of hydrogen, halogen, CN, OH, nitro, an        optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₀-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁹, C₀-C₆—NR⁹S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹, C₀-C₆-alkyl-NR⁹C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁹—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹—C(═O)—NR¹⁰, C₀-C₆-alkyl-NR⁹—C(═NR¹⁰NR¹¹,    C₀-C₆-alkyl-(C═NR⁹)NR¹⁰, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁹) or    C₀-C₆-alkyl-O—N═CR⁹ substituents;    -   R⁹, R¹⁰ and R¹¹ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, heterocycle;

-   B¹ represents independently C or N which may further be substituted    by G^(q) groups;

-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹², O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹²,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹², C₃-C₆-alkynyl-OR¹², C₃-C₆-alkenyl-OR¹²,    C₀-C₆-alkyl-S—R¹², O—C₂-C₆-alkyl-S—R¹², C₀-C₆-alkyl-S(═O)—R¹²,    O—C₂-C₆-alkyl-S(═O)—R¹², C₀-C₆-alkyl-S(═O)₂—R¹²,    O—C₁-C₆-alkyl-S(═O)₂—R¹², C₀-C₆-alkyl-NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²R¹³, C₀-C₆-alkyl-S(═O)₂NR¹²R¹³,    C₀-C₆-alkyl-NR¹²—S(═O)₂R¹³, O—C₁-C₆-alkyl-S(═O)₂NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²—S(═O)₂R¹³, C₀-C₆-alkyl-C(═O)—NR¹²R¹³,    C₀-C₆-alkyl-NR¹²C(═O)—R¹³, O—C₁-C₆-alkyl-C(═O)—NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²C(═O)—R¹³, C₀-C₆-alkyl-OC(═O)—R¹²,    C₀-C₆-alkyl-C(═O)—OR¹², O—C₂-C₆-alkyl-OC(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—OR¹², C₀-C₆-alkyl-C(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—R¹², C₀-C₆-alkyl-NR¹²—C(═O)—OR¹³,    C₀-C₆-alkyl-O—C(═O)—NR¹²R¹³ or C₀-C₆-alkyl-NR¹²—C(═O)—NR¹³R¹⁴    substituents; wherein optionally two substituents are combined to    the intervening atoms to form a bicyclic aryl, cycloalkyl,    heterocycloalkyl or heteroaryl ring; wherein each ring is optionally    further substituted with 1-5 independent halogen, CN, OH, nitro, an    optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl,    O—C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;

-   q is an integer from 1 to 5;    -   R¹², R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In a more preferred aspect of Formula II-A3, the compounds of thepresent invention are represented by Formula II-A3-a

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   R¹, R², R³ and R⁴ are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁵, O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR⁵,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR⁵, C₃-C₆-alkynyl-OR⁵, C₃-C₆-alkenyl-OR⁵,    C₀-C₆-alkyl-S—R⁵, O—C₂-C₆-alkyl-S—R⁵, C₀-C₆-alkyl-S(═O)—R⁵,    O—C₂-C₆-alkyl-S(═O)—R⁵, C₀-C₆-alkyl-S(═O)₂—R⁵,    O—C₁-C₆-alkyl-S(═O)₂—R⁵, C₀-C₆-alkyl-NR⁵R⁶, O—C₂-C₆-alkyl-NR⁵R⁶,    C₀-C₆-alkyl-S(═O)₂NR⁵R⁶, C₀-C₆-alkyl-NR⁵—S(═O)₂R⁶,    O—C₁-C₆-alkyl-S(═O)₂NR⁵R⁶, O—C₂-C₆-alkyl-NR⁵—S(═O)₂R⁶,    C₀-C₆-alkyl-C(═O)—NR⁵R⁶, C₀-C₆-alkyl-NR⁵C(═O)—R⁶,    O—C₁-C₆-alkyl-C(═O)—NR⁵R⁶, O—C₂-C₆-alkyl-NR⁵C(═O)—R⁶,    C₀-C₆-alkyl-OC(═O)—R⁵, C₀-C₆-alkyl-C(═O)—OR⁵,    O—C₂-C₆-alkyl-OC(═O)—R⁵, O—C₁-C₆-alkyl-C(═O)—OR⁵,    C₀-C₆-alkyl-C(═O)—R⁵, O—C₁-C₆-alkyl-C(═O)—R⁵,    C₀-C₆-alkyl-NR⁵—C(═O)—OR⁶, C₀-C₆-alkyl-O—C(═O)—NR⁵R⁶ or    C₀-C₆-alkyl-NR⁵—C(═O)—NR⁶R⁷ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁵, R⁶ and R⁷ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₀-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁸, C₀-C₆—NR⁸S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁸, C₀-C₆-alkyl-C(═O)—NR⁸, C₀-C₆-alkyl-NR⁸C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁸—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁸,    C₀-C₆-alkyl-NR⁸—C(═O)—NR⁹, C₀-C₆-alkyl-NR⁸—C(═NR⁹)NR¹⁰,    C₀-C₆-alkyl-(C═NR⁸)NR⁹, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁸—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁸) or    C₀-C₆-alkyl-O—N═CR⁸ substituents;    -   R⁸, R⁹ and R¹⁰ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;-   B¹ represent independently C or N which may further be substituted    by G^(q) groups;-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹¹, O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹¹,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹¹, C₃-C₆-alkynyl-OR¹¹, C₃-C₆-alkenyl-OR¹¹,    C₀-C₆-alkyl-S—R¹¹, O—C₂-C₆-alkyl-S—R¹¹, C₀-C₆-alkyl-S(═O)—R¹¹,    O—C₂-C₆-alkyl-S(═O)—R¹¹, C₀-C₆-alkyl-S(═O)₂—R¹¹,    O—C₁-C₆-alkyl-S(═O)₂—R¹¹, C₀-C₆-alkyl-NR¹¹R¹²,    O—C₂-C₆-alkyl-NR¹¹R¹², C₀-C₆-alkyl-S(═O)₂NR¹¹R¹²,    C₀-C₆-alkyl-NR¹⁰—S(═O)₂R¹², O—C₁-C₆-alkyl-S(═O)₂NR¹¹R¹²,    O—C₂-C₆-alkyl-NR¹⁰—S(═O)₂R¹², C₀-C₆-alkyl-C(═O)—NR¹¹R¹²,    C₀-C₆-alkyl-NR¹¹C(═O)—R¹², O—C₁-C₆-alkyl-C(═O)—NR¹¹R¹²,    O—C₂-C₆-alkyl-NR¹¹C(═O)—R¹², C₀-C₆-alkyl-OC(═O)—R¹¹,    C₀-C₆-alkyl-C(═O)—OR¹¹, O—C₂-C₆-alkyl-OC(═O)—R¹¹,    O—C₁-C₆-alkyl-C(═O)—OR¹¹, C₀-C₆-alkyl-C(═O)—R¹¹,    O—C₁-C₆-alkyl-C(═O)—R¹¹, C₀-C₆-alkyl-NR¹¹—C(═O)—OR¹²,    C₀-C₆-alkyl-O—C(═O)—NR¹¹R¹² or C₀-C₆-alkyl-NR¹¹—C(═O)—NR¹²R¹³    substituents; wherein optionally two substituents are combined to    the intervening atoms to form a bicyclic aryl, cycloalkyl,    heterocycloalkyl or heteroaryl ring; wherein each ring is optionally    further substituted with 1-5 independent halogen, CN, OH, nitro, an    optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl,    O—C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;-   q is an integer from 1 to 5;    -   R¹¹, R¹² and R¹³ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In a more preferred aspect of Formula II-A3-a, the compounds of thepresent invention are represented by Formula II-A3-a1 below

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   R¹, R², R³ and R⁴ are each independently selected from the group    consisting of hydrogen, halogen, an optionally substituted    C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₀-C₆-alkyl-OR⁵, C₀-C₆-alkyl-NR⁵R⁶,    C₀-C₆-alkyl-NR⁵C(═O)—R⁶ or C₀-C₆-alkyl-NR⁵S(═O)₂—R⁶ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁵ and R⁶ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        heteroaryl, C₁-C₆-alkyl-heteroaryl, aryl;-   X is selected from an optionally substituted C₁-C₆-alkyl and    C₁-C₆-alkylhalo;-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, O—C₁-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₂-C₆-alkyl-OR⁷, O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR⁷,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR⁷, C₀-C₆-alkyl-S(═O)—R⁷, O—C₂-C₆-alkyl-S(═O)—R⁷,    C₀-C₆-alkyl-S(═O)₂—R⁷, O—C₁-C₆-alkyl-S(═O)₂—R⁷, C₀-C₆-alkyl-NR⁷R⁸,    O—C₂-C₆-alkyl-NR⁷R⁸, C₀-C₆-alkyl-S(═O)₂NR⁷R⁸,    C₀-C₆-alkyl-NR⁷—S(═O)₂R⁸, O—C₁-C₆-alkyl-S(═O)₂NR⁷R⁸,    O—C₂-C₆-alkyl-NR⁷—S(═O)₂R⁸, C₀-C₆-alkyl-C(═O)—NR⁷R⁸,    C₀-C₆-alkyl-NR⁷C(═O)—R⁸, O—C₁-C₆-alkyl-C(═O)—NR⁷R⁸,    O—C₂-C₆-alkyl-NR⁷C(═O)—R⁸, C₀-C₆-alkyl-C(═O)—R⁷,    O—C₁-C₆-alkyl-C(═O)—R⁷ or C₀-C₆-alkyl-NR⁷—C(═O)—NR⁸R⁹ substituents;-   q is an integer from 1 to 4;    -   R⁷, R⁸ and R⁹ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In a second aspect, the compounds of the present invention arerepresented by Formula II-A3-a1 wherein the linker is specified as inthe formula II-A3-a2 depicted below

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   R¹, R², R³ and R⁴ are each independently selected from the group    consisting of hydrogen, halogen, an optionally substituted    C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₀-C₆-alkyl-OR⁵, C₀-C₆-alkyl-NR⁵R⁶,    C₀-C₆-alkyl-NR⁵C(═O)—R⁶ or C₀-C₆-alkyl-NR⁵S(═O)₂—R⁶ substituents;    -   R⁵ and R⁶ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₃-C₇-cycloalkyl, heteroaryl, aryl;-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, nitro, CN, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, O—C₀-C₆-alkyl,    O—C₀-C₆-alkylaryl, heteroaryl, aryl or C₀-C₆-alkyl-NR⁷R⁸    substituents;-   q is an integer from 1 to 4;    -   R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In a fourth aspect, the compounds of the present invention arerepresented by Formula II-A wherein the heterocyclic ring system isspecified as in the formula II-A4 depicted below

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from the group consisting of C, N, O and S;

provided that W is a heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₀-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁹, C₀-C₆—NR⁹S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹, C₀-C₆-alkyl-NR⁹C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁹—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹—C(═O)—NR¹⁰, C₀-C₆-alkyl-NR⁹—C(═NR¹⁰NR¹¹,    C₀-C₆-alkyl-(C═NR⁹)NR¹⁰, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁹) or    C₀-C₆-alkyl-O—N═CR⁹ substituents;    -   R⁹, R¹⁰ and R¹¹ are each independently selected from hydrogen,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, heterocycle;

-   B¹ and B² are each independently selected from —C═C—, —C(═O)—,    —S(═O)₂—, —C═N— or —C-which may further be substituted by G^(q)    groups;

-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹², O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹²,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹², C₃-C₆-alkynyl-OR¹², C₃-C₆-alkenyl-OR¹²,    C₀-C₆-alkyl-S—R¹², O—C₂-C₆-alkyl-S—R¹², C₀-C₆-alkyl-S(═O)—R¹²,    O—C₂-C₆-alkyl-S(═O)—R¹², C₀-C₆-alkyl-S(═O)₂—R¹²,    O—C₁-C₆-alkyl-S(═O)₂—R¹², C₀-C₆-alkyl-NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²R¹³, C₀-C₆-alkyl-S(═O)₂NR¹²R¹³,    C₀-C₆-alkyl-NR¹²—S(═O)₂R¹³, O—C₁-C₆-alkyl-S(═O)₂NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²—S(═O)₂R¹³, C₀-C₆-alkyl-C(═O)—NR¹²R¹³,    C₀-C₆-alkyl-NR¹²C(═O)—R¹³, O—C₁-C₆-alkyl-C(═O)—NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²C(═O)—R¹³, C₀-C₆-alkyl-OC(═O)—R¹²,    C₀-C₆-alkyl-C(═O)—OR¹², O—C₂-C₆-alkyl-OC(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—OR¹², C₀-C₆-alkyl-C(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—R¹², C₀-C₆-alkyl-NR¹²—C(═O)—OR¹³,    C₀-C₆-alkyl-O—C(═O)—NR¹²R¹³ or C₀-C₆-alkyl-NR¹²—C(═O)NR¹³R¹⁴    substituents; wherein optionally two substituents are combined to    the intervening atoms to form a bicyclic aryl, cycloalkyl,    heterocycloalkyl or heteroaryl ring; wherein each ring is optionally    further substituted with 1-5 independent hydrogen, halogen, CN, OH,    nitro, an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,    C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,    O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O-heteroaryl, heteroaryl, C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;

-   q is an integer from 1 to 5;    -   R¹², R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

Particularly preferred compounds of the present invention are compoundsof Formula II-B

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from the group consisting of C, N, O and S; provided that W is a    heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₀-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁹, C₀-C₆—NR⁹S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹, C₀-C₆-alkyl-NR⁹C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁹—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹—C(═O)—NR¹⁰, C₀-C₆-alkyl-NR⁹—C(═NR¹⁰NR¹¹,    C₀-C₆-alkyl-(C═NR⁹)NR¹⁰, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁹) or    C₀-C₆-alkyl-O—N═CR⁹ substituents;    -   R⁹, R¹⁰ and R¹¹ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, heterocycle;

-   Z⁹, Z¹⁰, Z¹¹ and Z¹² are each independently selected from the group    consisting of —C═, —C═C—, —C—, —O—, —N═, —N— or —S— which may    further be substituted by 1 to 4 G^(q) groups;

-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹², O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹²,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹², C₃-C₆-alkynyl-OR¹², C₃-C₆-alkenyl-OR¹²,    C₀-C₆-alkyl-S—R¹², O—C₂-C₆-alkyl-S—R¹², C₀-C₆-alkyl-S(═O)—R¹²,    O—C₂-C₆-alkyl-S(═O)—R¹², C₀-C₆-alkyl-S(═O)₂—R¹²,    O—C₁-C₆-alkyl-S(═O)₂—R¹², C₀-C₆-alkyl-NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²R¹³, C₀-C₆-alkyl-S(═O)₂NR¹²R¹³,    C₀-C₆-alkyl-NR¹²—S(═O)₂R¹³, O—C₁-C₆-alkyl-S(═O)₂NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²—S(═O)₂R¹³, C₀-C₆-alkyl-C(═O)—NR¹²R¹³,    C₀-C₆-alkyl-NR¹²C(═O)—R¹³, O—C₁-C₆-alkyl-C(═O)—NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²C(═O)—R¹³, C₀-C₆-alkyl-OC(═O)—R¹²,    C₀-C₆-alkyl-C(═O)—O—R¹², O—C₂-C₆-alkyl-OC(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—OR¹², C₀-C₆-alkyl-C(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—R¹², C₀-C₆-alkyl-NR¹²—C(═O)—OR¹³,    C₀-C₆-alkyl-O—C(═O)—NR¹²R¹³ or C₀-C₆-alkyl-NR¹²—C(═O)—NR¹³R¹⁴    substituents;

wherein optionally two substituents are combined to the interveningatoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl orheteroaryl ring; wherein each ring is optionally further substitutedwith 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionallysubstituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl,O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;

-   q is an integer from 1 to 4;    -   R¹², R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In one aspect, the compounds of the present invention are represented byFormula II-B wherein the heterocyclic ring system is specified as in theformula II-B1 depicted below

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from the group consisting of C, N, O and S; provided that W is a    heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₀-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁹, C₀-C₆—NR⁹S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹, C₀-C₆-alkyl-NR⁹C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁹—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹—C(═O)—NR¹⁰, C₀-C₆-alkyl-NR⁹—C(═NR¹⁰NR¹¹,    C₀-C₆-alkyl-(C═NR⁹)NR¹⁰, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁹) or    C₀-C₆-alkyl-O—N═CR⁹ substituents;    -   R⁹, R¹⁰ and R¹¹ are each independently selected from hydrogen,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, heterocycle;

-   B¹ represents independently C or N which may further be substituted    by G^(q) groups;

-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹², O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹²,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹², C₃-C₆-alkynyl-OR¹², C₃-C₆-alkenyl-OR¹²,    C₀-C₆-alkyl-S—R¹², O—C₂-C₆-alkyl-S—R¹², C₀-C₆-alkyl-S(═O)—R¹²,    O—C₂-C₆-alkyl-S(═O)—R¹², C₀-C₆-alkyl-S(═O)₂—R¹²,    O—C₁-C₆-alkyl-S(═O)₂—R¹², C₀-C₆-alkyl-NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²R¹³, C₀-C₆-alkyl-S(═O)₂NR¹²R¹³,    C₀-C₆-alkyl-NR¹²—S(═O)₂R¹³, O—C₁-C₆-alkyl-S(═O)₂NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²—S(═O)₂R¹³, C₀-C₆-alkyl-C(═O)—NR¹²R¹³,    C₀-C₆-alkyl-NR¹²C(═O)—R¹³, O—C₁-C₆-alkyl-C(═O)—NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²C(═O)—R¹³, C₀-C₆-alkyl-OC(═O)—R¹²,    C₀-C₆-alkyl-C(═O)—OR¹², O—C₂-C₆-alkyl-OC(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—OR¹², C₀-C₆-alkyl-C(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—R¹², C₀-C₆-alkyl-NR¹²—C(═O)—OR¹³,    C₀-C₆-alkyl-O—C(═O)—NR¹²R¹³ or C₀-C₆-alkyl-NR¹²—C(═O)—NR¹³R¹⁴    substituents; wherein optionally two substituents are combined to    the intervening atoms to form a bicyclic aryl, cycloalkyl,    heterocycloalkyl or heteroaryl ring; wherein each ring is optionally    further substituted with 1-5 independent halogen, CN, OH, nitro, an    optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl,    O—C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;

-   q is an integer from 1 to 2;    -   R¹², R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In a second aspect, the compounds of the present invention arerepresented by Formula II-B wherein the heterocyclic ring system isspecified as in the formula II-B2 depicted below

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from the group consisting of C, N, O and S; provided that W is a    heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₀-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁹, C₀-C₆—NR⁹S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹, C₀-C₆-alkyl-NR⁹C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁹—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹—C(═O)—NR¹⁰, C₀-C₆-alkyl-NR⁹—C(═NR¹⁰NR¹¹,    C₀-C₆-alkyl-(C═NR⁹)NR¹⁰, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁹) or    C₀-C₆-alkyl-O—N═CR⁹ substituents;    -   R⁹, R¹⁰ and R¹¹ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, heterocycle;

-   B¹ represents independently C or N which may further be substituted    by one G^(q) group;

-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹², O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹²,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹², C₃-C₆-alkynyl-OR¹², C₃-C₆-alkenyl-OR¹²,    C₀-C₆-alkyl-S—R¹², O—C₂-C₆-alkyl-S—R¹², C₀-C₆-alkyl-S(═O)—R¹²,    O—C₂-C₆-alkyl-S(═O)—R¹², C₀-C₆-alkyl-S(═O)₂—R¹²,    O—C₁-C₆-alkyl-S(═O)₂—R¹², C₀-C₆-alkyl-NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²R¹³, C₀-C₆-alkyl-S(═O)₂NR¹²R¹³,    C₀-C₆-alkyl-NR¹²—S(═O)₂R¹³, O—C₁-C₆-alkyl-S(═O)₂NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²—S(═O)₂R¹³, C₀-C₆-alkyl-C(═O)—NR¹²R¹³,    C₀-C₆-alkyl-NR¹²C(═O)—R¹³, O—C₁-C₆-alkyl-C(═O)—NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²C(═O)—R¹³, C₀-C₆-alkyl-OC(═O)—R¹²,    C₀-C₆-alkyl-C(═O)—OR¹², O—C₂-C₆-alkyl-OC(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—OR¹², C₀-C₆-alkyl-C(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—R¹², C₀-C₆-alkyl-NR¹²—C(═O)—OR¹³,    C₀-C₆-alkyl-O—C(═O)—NR¹²R¹³ or C₀-C₆-alkyl-NR¹²—C(═O)—NR¹³R¹⁴    substituents; wherein optionally two substituents are combined to    the intervening atoms to form a bicyclic aryl, cycloalkyl,    heterocycloalkyl or heteroaryl ring; wherein each ring is optionally    further substituted with 1-5 independent halogen, CN, OH, nitro, an    optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl,    O—C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;

-   q is an integer from 1 to 3;    -   R¹², R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

Further preferred compounds of the present invention are compounds ofFormula II-C

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from the group consisting of C, N, O and S; provided that W is a    heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₀-C₆-alkyl,    O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,    O—C₃-C₇-cycloalkyl, C₀-C₆-alkyl-O, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₀-C₆-alkyl, S—C₀-C₆-alkyl, C₁-C₆-alkylhalo-O,    C₃-C₆-alkynyl-O, C₃-C₆-alkenyl-O, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O),    C₀-C₆-alkyl-S(═O)₂, C₀-C₆-alkyl-NR⁹, C₀-C₆—NR⁹S(═O)₂,    C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹, C₀-C₆-alkyl-NR⁹C(═O),    C₀-C₆-alkyl-OC(═O), C₀-C₆-alkyl-C(═O)—O, C₀-C₆-alkyl-C(═O),    C₀-C₆-alkyl-NR⁹—C(═O)—O, C₀-C₆-alkyl-O—C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹—C(═O)—NR¹⁰, C₀-C₆-alkyl-NR⁹—C(═NR¹⁰NR¹¹,    C₀-C₆-alkyl-(C═NR⁹)NR¹⁰, C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-C(═NOR⁹) or    C₀-C₆-alkyl-O—N═CR⁹ substituents;    -   R⁹, R¹⁰ and R¹¹ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, heterocycle;

-   B¹, B² and B³ are each independently selected from C or N which may    further be substituted by G^(q) groups;

-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹², O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR¹²,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹², C₃-C₆-alkynyl-OR¹², C₃-C₆-alkenyl-OR¹²,    C₀-C₆-alkyl-S—R¹², O—C₂-C₆-alkyl-S—R¹², C₀-C₆-alkyl-S(═O)—R¹²,    O—C₂-C₆-alkyl-S(═O)—R¹², C₀-C₆-alkyl-S(═O)₂—R¹²,    O—C₁-C₆-alkyl-S(═O)₂—R¹², C₀-C₆-alkyl-NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²R¹³, C₀-C₆-alkyl-S(═O)₂NR¹²R¹³,    C₀-C₆-alkyl-NR¹²—S(═O)₂R¹³, O—C₁-C₆-alkyl-S(═O)₂NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²—S(═O)₂R¹³, C₀-C₆-alkyl-C(═O)—NR¹²R¹³,    C₀-C₆-alkyl-NR¹²C(═O)—R¹³, O—C₁-C₆-alkyl-C(═O)—NR¹²R¹³,    O—C₂-C₆-alkyl-NR¹²C(═O)—R¹³, C₀-C₆-alkyl-OC(═O)—R¹²,    C₀-C₆-alkyl-C(═O)—OR¹², O—C₂-C₆-alkyl-OC(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—OR¹², C₀-C₆-alkyl-C(═O)—R¹²,    O—C₁-C₆-alkyl-C(═O)—R¹², C₀-C₆-alkyl-NR¹²—C(═O)—OR¹³,    C₀-C₆-alkyl-O—C(═O)—NR¹²R¹³ or C₀-C₆-alkyl-NR¹²—C(═O)—NR¹³R¹⁴    substituents; wherein optionally two substituents are combined to    the intervening atoms to form a bicyclic aryl, cycloalkyl,    heterocycloalkyl or heteroaryl ring; wherein each ring is optionally    further substituted with 1-5 independent halogen, CN, OH, nitro, an    optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl,    O—C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;

-   q is an integer from 1 to 5;    -   R¹², R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;        provided that:    -   when X is independently selected from NR¹⁵, O, S or an        optionally substituted C₁-C₆-alkyl, G^(q) and q are as defined        above, W is an optionally substituted 2-pyridinyl and R¹⁵ is        independently selected from hydrogen, an optionally substituted        C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl,        C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl or aryl, B₁, B₂ and B₃ can not be C;    -   when X is O, B¹, B² and B³ are each independently selected from        C or N, G^(q) and q are as defined above, W can not be an        optionally substituted 3-pyridazinyl or 4-pyrimidinyl;    -   when X is CH₂, B¹, B² and B³ are C and G^(q) and q are as        defined above, W can not be 2-phenyloxazol-4-yl,        4-phenyloxazol-2-yl, 4-(3-(benzyloxy)propyl)-oxazol-2-yl,        4-phenylthiazol-2-yl, 4-methylthiazol-2-yl, benzo[d]oxazol-2-yl        or benzo[d]thiazol-2-yl;    -   when X is O, W is an optionally substituted pyridinyl and G^(q)        and q are as defined above, B¹, B² or B³ can not be N;    -   when X is CH₂CH₂, B¹, B² and B³ are C and G^(q) and q are as        defined above, W can not be 4-imidazolyl.    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

In a more preferred aspect of formula II-C

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from the group consisting of C, N, O and S; provided that W is a    heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₂-C₆-alkynyl,    C₀-C₆-alkyl-NR⁹S(═O)₂, C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹C(═O), C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C₀-C₆-alkyl-OC(═O) or    C₀-C₆-alkyl-C(═O)-0 substituents;    -   R⁹ is selected from hydrogen, an optionally substituted        C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;

-   B¹, B² and B³ are each independently selected from C or N which may    further be substituted by G^(q) groups;    -   G^(q) groups are each independently selected from the group        consisting of hydrogen, halogen, CN, OH, nitro, an optionally        substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,        C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹⁰,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR′°, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O-heteroaryl, heteroaryl, C₁-C₆-alkyl-heteroaryl, aryl, O-aryl,        C₁-C₆-alkylaryl, C₁-C₆-alkylhalo-OR¹⁰, C₃-C₆-alkynyl-OR¹⁰,        C₃-C₆-alkenyl-OR¹⁰, C₀-C₆-alkyl-S—R¹⁰, O—C₂-C₆-alkyl-S—R¹⁰,        C₀-C₆-alkyl-S(═O)—R¹⁰, O—C₂-C₆-alkyl-S(═O)—R¹⁰,        C₀-C₆-alkyl-S(═O)₂—R¹⁰, O—C₁-C₆-alkyl-S(═O)₂—R¹⁰,        C₀-C₆-alkyl-NR¹⁰R¹¹, O—C₂-C₆-alkyl-NR¹⁰R¹¹,        C₀-C₆-alkyl-S(═O)₂NR¹⁰R¹¹, C₀-C₆-alkyl-NR¹⁰—S(═O)₂R¹¹,        O—C₁-C₆-alkyl-S(═O)₂NR¹⁰R¹¹, O—C₂-C₆-alkyl-NR¹⁰—S(═O)₂R¹¹,        C₀-C₆-alkyl-C(═O)—NR¹⁰R¹¹, C₀-C₆-alkyl-NR¹⁰C(═O)—R¹¹,        O—C₁-C₆-alkyl-C(═O)—NR¹⁰R¹¹, O—C₂-C₆-alkyl-NR¹⁰C(═O)—R¹¹,        C₀-C₆-alkyl-OC(═O)—R¹⁰, C₀-C₆-alkyl-C(═O)—OR¹⁰,        O—C₂-C₆-alkyl-OC(═O)—R¹⁰, O—C₁-C₆-alkyl-C(═O)—OR¹⁰,        C₀-C₆-alkyl-C(═O)—R¹⁰, O—C₁-C₆-alkyl-C(═O)—R¹⁰,        C₀-C₆-alkyl-NR₁₀—C(═O)—OR¹¹, C₀-C₆-alkyl-O—C(═O)—NR¹⁰R¹¹ or        C₀-C₆-alkyl-NR¹⁰—C(═O)—NR¹¹R¹² substituents;

-   q is an integer from 1 to 5;    -   R¹⁰, R¹¹ and R¹² are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.    -   In a second more preferred aspect of formula II-C

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a 5-, 6-heterocyclic ring containing a N adjacent to the    ethynyl bond, which ring may optionally be fused with a 5- or    6-membered ring containing one or more atoms independently selected    from a group consisting of C, N, O and S; provided that W can not be    a pyridine and W is a heteroaryl selected from the group of formula:

-   -   R¹, R², R³, R⁴, R⁵ and A^(m) are each independently selected        from the group consisting of hydrogen, halogen, CN, OH, nitro,        an optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo,        C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo,        O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR⁶,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₀-C₆-alkyl-OR⁶, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,        C₁-C₆-alkylhalo-OR⁶, C₃-C₆-alkynyl-OR⁶, C₃-C₆-alkenyl-OR⁶,        C₀-C₆-alkyl-S—R⁶, O—C₂-C₆-alkyl-S—R⁶, C₀-C₆-alkyl-S(═O)—R⁶,        O—C₂-C₆-alkyl-S(═O)—R⁶, C₀-C₆-alkyl-S(═O)₂—R⁶,        O—C₁-C₆-alkyl-S(═O)₂—R⁶, C₀-C₆-alkyl-NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶R⁷,        C₀-C₆-alkyl-S(═O)₂NR⁶R⁷, C₀-C₆-alkyl-NR⁶—S(═O)₂R⁷,        O—C₁-C₆-alkyl-S(═O)₂NR⁶R⁷, O—C₁-C₆-alkyl-NR⁶—S(═O)₂R⁷,        C₀-C₆-alkyl-C(═O)—NR⁶R⁷, C₀-C₆-alkyl-NR⁶C(═O)—R⁷,        O—C₁-C₆-alkyl-C(═O)—NR⁶R⁷, O—C₂-C₆-alkyl-NR⁶C(═O)—R⁷,        C₀-C₆-alkyl-OC(═O)—R⁶, C₀-C₆-alkyl-C(═O)—OR⁶,        O—C₂-C₆-alkyl-OC(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—OR⁶,        C₀-C₆-alkyl-C(═O)—R⁶, O—C₁-C₆-alkyl-C(═O)—R⁶,        C₀-C₆-alkyl-NR⁶—C(═O)—OR⁷, C₀-C₆-alkyl-O—C(═O)—NR⁶R⁷ or        C₀-C₆-alkyl-NR⁶—C(═O)—NR⁷R⁸ substituents;    -   wherein optionally two substituents are combined to the        intervening atoms to form a bicyclic aryl, cycloalkyl,        heterocycloalkyl or heteroaryl ring; wherein each ring is        optionally further substituted with 1-5 independent hydrogen,        halogen, CN, OH, nitro, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, O—C₁-C₆-alkyl,        O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl, O—C₃-C₆-alkenyl,        O—C₃-C₇-cycloalkyl, O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl,        C₁-C₆-alkylaryl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl, O-aryl;    -   R⁶, R⁷ and R⁸ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷ and Z⁸ are each independently        selected from the group consisting of —C═, —C═C—, —O—, —N═, —N—        or —S— which may further be substituted by 1 to 5 A^(m) groups;    -   m is an integer from 1 to 5;

-   X is selected from an optionally substituted C₁-C₆-alkyl,    C₂-C₆-alkynyl, O—C₀-C₆-alkyl, C₀-C₆-alkyl-O, O—C₃-C₆-alkynyl,    S—C₀-C₆-alkyl, C₀-C₆-alkyl-S, C₀-C₆-alkyl-S(═O), C₀-C₆-alkyl-S(═O)₂,    S(═O)₂—C₀-C₆-alkyl-, C₀-C₆-alkyl-NR⁹, NR⁹—C₀-C₆-alkyl,    C₀-C₆—NR⁹S(═O)₂, C₀-C₆-alkyl-S(═O)₂NR⁹, C₀-C₆-alkyl-C(═O)—NR⁹,    C₀-C₆-alkyl-NR⁹C(═O), C₀-C₆-alkyl-C(═O)—O—C₀-C₆-alkyl,    C₀-C₆-alkyl-C(═O)—NR⁹—C₀-C₆-alkyl, C(═O)—C₀-C₆-alkyl or    C₀-C₆-alkyl-C(═O) substituents;    -   R⁹ is selected from hydrogen, an optionally substituted        C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl,        C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;

-   B¹, B² and B³ are each independently selected from C or N which may    further be substituted by G^(q) groups;

-   G^(q) groups are each independently selected from the group    consisting of hydrogen, halogen, CN, OH, nitro, an optionally    substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, O—C₁-C₆-alkyl, O—C₁-C₆-alkylhalo, O—C₃-C₆-alkynyl,    O—C₃-C₆-alkenyl, O—C₂-C₆-alkyl-OR¹⁰, O—C₃-C₇-cycloalkyl,    O—C₁-C₆-alkyl-heteroaryl, O—C₁-C₆-alkylaryl, C₀-C₆-alkyl-OR′°,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,    O—C₃-C₇-cycloalkyl-C₁-C₆-alkyl, O-heteroaryl, heteroaryl,    C₁-C₆-alkyl-heteroaryl, aryl, O-aryl, C₁-C₆-alkylaryl,    C₁-C₆-alkylhalo-OR¹⁰, C₃-C₆-alkynyl-OR¹⁰, C₃-C₆-alkenyl-OR¹⁰,    C₀-C₆-alkyl-S—R¹⁰, O—C₂-C₆-alkyl-S—R¹⁰, C₀-C₆-alkyl-S(═O)—R¹⁰,    O—C₂-C₆-alkyl-S(═O)—R¹⁰, C₀-C₆-alkyl-S(═O)₂—R¹⁰,    O—C₁-C₆-alkyl-S(═O)₂—R¹⁰, C₀-C₆-alkyl-NR¹⁰R¹¹,    O—C₂-C₆-alkyl-NR¹⁰R¹¹, C₀-C₆-alkyl-S(═O)₂NR¹⁰R¹¹,    C₀-C₆-alkyl-NR¹⁰—S(═O)₂R¹¹, O—C₁-C₆-alkyl-S(═O)₂NR¹⁰R¹¹,    O—C₂-C₆-alkyl-NR¹⁰—S(═O)₂R¹¹, C₀-C₆-alkyl-C(═O)—NR¹⁰R¹¹,    C₀-C₆-alkyl-NR¹⁰C(═O)—R¹¹, O—C₁-C₆-alkyl-C(═O)—NR¹⁰R¹¹,    O—C₂-C₆-alkyl-NR¹⁰C(═O)—R¹¹, C₀-C₆-alkyl-OC(═O)—R¹⁰,    C₀-C₆-alkyl-C(═O)—OR¹⁰, O—C₂-C₆-alkyl-OC(═O)—R¹⁰,    O—C₁-C₆-alkyl-C(═O)—OR¹⁰, C₀-C₆-alkyl-C(═O)—R¹⁰,    O—C₁-C₆-alkyl-C(═O)—R¹⁰, C₀-C₆-alkyl-NR¹⁰—C(═O)—OR¹¹,    C₀-C₆-alkyl-O—C(═O)—NR¹⁰R¹¹ or C₀-C₆-alkyl-NR¹⁰—C(═O)—NR¹¹R¹²    substituents;

-   q is an integer from 1 to 5;    -   R¹⁰, R¹¹ and R¹² are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkyl, heteroaryl,        C₁-C₆-alkyl-heteroaryl, aryl;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well;        provided that:    -   when X is O, B¹, B² and B³ are each independently selected from        C or N, G^(q) and q are as defined above, W can not be an        optionally substituted 3-pyridazinyl or 4-pyrimidinyl;    -   when X is CH₂, B¹, B² and B³ are C and G^(q) and q are as        defined above, W can not be 2-phenyloxazol-4-yl,        4-phenyloxazol-2-yl, 4-(3-(benzyloxy)propyl)-oxazol-2-yl,        4-phenylthiazol-2-yl, 4-methylthiazol-2-yl, benzo[d]oxazol-2-yl        or benzo[d]thiazol-2-yl;    -   when X is CH₂CH₂, B¹, B² and B³ are C and G^(q) and q are as        defined above, W can not be 4-imidazolyl.    -   In a more preferred aspect of formula II

Or a pharmaceutically acceptable salt, hydrate or solvate of suchcompound

Wherein

-   W is a heteroaryl selected from the group of formula:

-   -   R¹, R², R³ and R⁴ are each independently selected from the group        consisting of hydrogen, halogen, an optionally substituted        C₁-C₆-alkyl, C₁-C₆-alkylhalo, aryl, C₀-C₆-alkyl-OR⁵,        C₀-C₆-alkyl-NR⁵R⁶, C₀-C₆-alkyl-NR⁵C(═O)—R⁶ or        C₀-C₆-alkyl-NR⁵S(═O)₂—R⁶ substituents;    -   R⁵ and R⁶ are each independently selected from the group        consisting of hydrogen, an optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkylhalo, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkyl,        heteroaryl, C₁-C₆-alkyl-heteroaryl, aryl;

-   X is selected from an optionally substituted C₁-C₆-alkyl or    C₁-C₆-alkylhalo;

-   W′ is selected from:

-   -   G^(q) groups are each independently selected from the group        consisting of hydrogen, halogen, nitro, an optionally        substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo, C₀-C₆-alkyl-OR⁷,        O—C₀-C₆-alkylaryl, heteroaryl, aryl, C₀-C₆-alkyl-NR⁷R⁸ or        C₀-C₆-alkyl-NR⁷—S(═O)₂R⁸ substituents;    -   q is an integer from 1 to 5;    -   R⁷ and R⁸ are each independently selected from hydrogen, an        optionally substituted C₁-C₆-alkyl, C₁-C₆-alkylhalo;    -   Any N may be an N-oxide;    -   The present invention includes both possible stereoisomers and        includes not only racemic compounds but the individual        enantiomers as well.

Specifically preferred compounds are:

-   2-Methyl-(4-(4-phenyl)but-1-ynyl)thiazole-   2-(4-(3-(2-Ethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(Pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione-   2-(4-(Pyridin-2-yl)but-3-ynyl)phthalazin-1(2H)-one-   2-(4-Phenylbut-1-ynyl)quinoline-   2-(4-Phenylbut-1-ynyl)pyrimidine-   2-(4-Phenylbut-1-ynyl)benzo[d]oxazole-   2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole hydrochloride-   2-(4-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-Phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-Methyl-4-(4-phenylbut-1-ynyl)-1H-imidazole-   N-Methyl-N-phenyl-5-(pyridin-2-yl)pent-4-ynamide-   N-(4-Fluorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide-   2-(4-(2-Phenylthiazol-4-yl)but-1-ynyl)pyridine-   2-(4-(3-o-Tolyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-benzyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2-Methylbenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(4-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(4-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-Isopropyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-Butyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(3-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(3-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   5-Chloro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   5-Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   6-Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   4-Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)benzo[d]oxazole-   2-(4-(5-Phenyl-2H-tetrazol-2-yl)but-1-ynyl)pyridine-   N-(4-Fluorophenyl)-5-(pyridine-2-yl)pent-4-ynamide-   2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   6-Chloro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   5-Fluoro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   2-(6-(4-Fluorophenyl)hexa-1,5-diynyl)pyridine-   2-(4-(3-(2-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(3-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-m-Tolyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-p-Tolyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2-Chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2,6-Dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2-Trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(Naphthalen-1-yl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(Naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2,3-dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2,5-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2,6-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2,3-dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2-chloro-6-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(5-Fluoro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(5-Chloro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(3-(2-(Trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   6-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   7-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   7-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   2-(4-(5-Phenyloxazol-2-yl)but-1-ynyl)pyridine-   2-(4-(3-(3-Chloro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine-   2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-4-ol-   2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   4-Methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   2-(4-(Pyridin-2-yl)but-3-ynyl)oxazolo[5,4-b]pyridine-   7-Chloro-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   2-(4-(Pyridin-2-yl)but-3-ynyl)oxazolo[4,5-b]pyridine-   2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-5-carbonitrile-   7-Chloro-5-fluoro-2-(4-(2-methylthiazol-4-yl)but-3-ynyl)benzo[d]oxazole-   7-(Trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   7-Bromo-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   5-Fluoro-7-phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   2-(4-(2-Chloropyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole-   2-Chloro-4-(4-phenylbut-1-ynyl)pyrimidine-   4-Bromo-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   4-Phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   5,7-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   4-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   7-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-7-carbonitrile-   7-Chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   7-Methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   7-Isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   4,7-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   7-Fluoro-4-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   2-(4-(Pyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole-   N-(3-Chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide-   7-Chloro-4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   4-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   4,7-Dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   4-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   5-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   N-(2-Chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide-   1-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole-   2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-indazole-   1-(4-(pyridin-2-yl)but-3-ynyl)-1H-indazole-   2-(4-(5-Phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine-   2-(4-(3-Phenylisoxazol-5-yl)but-1-ynyl)pyridine-   2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)benzo[d]thiazole-   2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   2-(4-(6-Methylpyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   2-(4-(6-Chloropyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   7-Chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   2-(4-(6-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   2-(4-(Pyridin-2-yl)but-3-ynyl)quinoline-   2-(4-(4-Phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine-   7-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole-   2-(6-(Pyridin-2-yl)hex-5-ynyl)-2H-indazole-   1-(6-(pyridin-2-yl)hex-5-ynyl)-1H-indazole-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoline-   2-(4-(6-Methylpyridin-2-yl)but-3-ynyl)quinoline-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole-   2-(4-(4-(4-Fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine-   2-(4-(4-o-Tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine-   2-(Fluoromethyl)-6-(4-(4-o-tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine-   2-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine-   6-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline-   6,7-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline-   4-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole-   4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole-   6-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole-   4-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole-   7-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole-   2-(4-(3-Phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine-   2-(4-(3-(4-Fluorophenyl)isoxazol-5-yl)but-1-ynyl)pyridine-   2(4(5-(4-Fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine-   2-(1-Fluoro-4-(pyridin-2-yl)but-3-ynyl)quinoxaline-   2-(4-(3-Methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine-   2-(4-(5-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine-   2-(4-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-3-methylquinoxaline-   2-(4-(Pyridin-2-yl)but-3-ynyl)isoquinolin-1(2H)-one-   2,6-Dimethoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   2,6-Difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   5-(6-(Fluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)pent-4-ynamide-   2-(4-(Pyridin-2-yl)but-3-ynyl)isoindolin-1-one-   N-(2-Fluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide-   N-(3-Fluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide-   N-(4-Fluoro-2-methyl-phenyl)-5-(pyridin-2-yl)pent-4-ynamide-   2,6-Dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide-   2-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide-   2-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzenesulfonamide-   2-Chloro-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide-   5-(6-(Fluoromethyl)pyridin-2-yl)-N-(4-fluoro-2-methyl-phenyl)pent-4-ynamide-   5-(4-Fluoro-phenyl)-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one-   2-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine-   2-(4-(4-(4-Fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine-   2-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine-   2-(4-(4-(4-Fluorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine-   2-(4-(4-(4-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine-   2-(4-(4-(2-Chlorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine-   1-(4-(4-(2-Chlorophenyl)-1H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole-   7-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole-   7-Chloro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole-   4,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole-   1-Isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole-   1-Phenethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole-   1-Benzyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole-   5-Fluoro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole-   1-(4-(Pyridin-2-yl)but-3-ynyl)pyridin-2(1H)-one-   3-Methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   3-Fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   N-Methyl-2-phenyl-N-(4-(pyridin-2-yl)but-3-ynyl)acetamide-   N-Methyl-N-(4-(pyridin-2-yl)but-3-ynyl)-2-(trifluoromethyl)benzamide-   4-Fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   2-Chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   3-Chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   4-Fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide-   2-Chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide-   2-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide-   2-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzene    sulfonamide-   2,6-Dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide-   N-Methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   N,2-Dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   2-Fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   N,4-Dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   N,3-Dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   2-Methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   2,3-Difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   2,6-Dichloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide-   N,3,5-Trimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)isoxazole-4-sulfonamide-   N-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]thiazol-2-amine-   1-Methyl-3-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d]imidazol-2(3H)-one-   (3-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole-   2-(4-(2-Methyl-1H-imidazol-4-yl)but-3-ynyl)benzo[d]oxazole-   2-(4-(1,2-Dimethyl-1H-imidazol-4-yl)but-3-ynyl)benzo[d]oxazole-   4-(Pyridin-2-yl)but-3-ynyl 2-chlorobenzoate-   4-(Pyridin-2-yl)but-3-ynyl 3-chlorobenzoate-   3-Chlorophenyl 5-(pyridin-2-yl)pent-4-ynoate-   3-Chlorophenyl 5-(3-fluoropyridin-2-yl)pent-4-ynoate-   2-Chlorophenyl 5-(pyridin-2-yl)pent-4-ynoate-   2-Chlorophenyl 5-(2-methylthiazol-4-yl)pent-4-ynoate-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)benzo[d]thiazole-   2-(5-(Pyridin-2-yl)pent-4-ynyl)isoindoline-1,3-dione-   2-(6-(Pyridin-2-yl)hex-5-ynyl)phthalazin-1(2H)-one-   1-Methyl-3-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d]imidazol-2(3H)-one-   N-(4-Chlorophenyl)-5-(pyridin-2-yl)pent-4-ynamide-   N-(3-Chlorophenyl)-5-(pyridin-2-yl)pent-4-ynamide-   N-(2,4-Difluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide-   2-(4-(Pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   8-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   5-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   5-Phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)imidazo[1,2-a]pyridine-   6-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   1-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d][1,2,3]triazole-   2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole    hydrochloride-   2-(5-(Pyridin-2-yl)pent-4-ynyl)-2H-benzo[d][1,2,3]triazole-   1-(5(Pyridin-2-yl)pent-4-ynyl)-1H-benzo[d][1,2,3]triazole-   1-(6-(Pyridin-2-yl)hex-5-ynyl)-1H-benzo[d][1,2,3]triazole-   2-(6-(pyridin-2-yl)hex-5-ynyl)-2H-benzo[d][1,2,3]triazole-   5-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole    hydrochloride-   4,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   4,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole    hydrochloride-   4,5-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   4,5-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole    hydrochloride-   2-(4-(6-(Difluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   4,6-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   4,5-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   2-(4-(6-Methylpyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   2(4-(3-Fluoropyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   5-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   4-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   5,6-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   5,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   4-Chloro-2-(4-(1-methyl-1H-pyrazol-3-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   6-(4-(4,6-Difluoro-2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-amine-   2-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-6-methylpyridin-3-amine-   4-Nitro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-nitro-2H-benzo[d][1,2,3]triazole-   2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazol-4-amine-   4-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-methyl-2H-benzo[d][1,2,3]triazole-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-5-methyl-2H-benzo[d][1,2,3]triazole-   5-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-methylpyridin-2-amine-   N-(6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)acetamide-   6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-ethylpyridin-2-amine-   N-(6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)methylsulfonamide-   N-(6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)formamide-   4-Chloro-2-(4-(1,2-dimethyl-1H-imidazol-4-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   4,5-Dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-4,5-dimethyl-2H-benzo[d][1,2,3]triazole-   2-(4-(6-Chloropyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   2-(4-(6-(1-Fluoroethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   2(4(4,5-Dimethylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   2-(4-(Pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one-   2-(4-(4-Methylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole-   8-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   8-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   6-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine-   6-Fluoro-2-(4-(2-(fluoromethyl)thiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   8-Bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   8-(Benzyloxy)-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-8-phenyl-imidazo[1,2-a]pyridine-   6,8-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine-   6,8-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine

The present invention relates to the pharmaceutically acceptable acidaddition salts of compounds of the formula (I) or pharmaceuticallyacceptable carriers or excipients.

The present invention relates to a method of treating or preventing acondition in a mammal, including a human, the treatment or prevention ofwhich is affected or facilitated by the neuromodulatory effect of mGluR5antagonists.

The present invention relates to a method useful for treating orpreventing peripheral and central nervous system disorders selected fromthe group consisting of: substance tolerance or dependence, anxietydisorders, depression, mood disorders, psychiatric disease such aspsychosis, inflammatory or neuropathic pain, Fragile X syndrome, autism,memory deficits, Alzheimer's disease, Parkinson's disease, migraine,ischemia, drug abuse and addiction.

The present invention relates to pharmaceutical compositions whichprovide from about 0.01 to 1000 mg of the active ingredient per unitdose. The compositions may be administered by any suitable route. Forexample orally in the form of capsules, etc. . . . , parenterally in theform of solutions for injection, topically in the form of onguents orlotions, ocularly in the form of eye-drops, rectally in the form ofsuppositories, intranasally or transcutaneously in the form of deliverysystem like patches.

The pharmaceutical formulations of the invention may be prepared byconventional methods in the art; the nature of the pharmaceuticalcomposition employed will depend on the desired route of administration.The total daily dose usually ranges from about 0.05-2000 mg.

Methods of Synthesis

Compounds of general formula I may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (Green T. W. and Wuts P. G. M. (1991) ProtectingGroups in Organic Synthesis, John Wiley et Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprocess as well as the reaction conditions and order of their executionshall be consistent with the preparation of compounds of formula I.

The compound of formula I may be represented as a mixture ofenantiomers, which may be resolved into the individual pure R- orS-enantiomers. If for instance, a particular enantiomer of the compoundof formula I is desired, it may be prepared by asymmetric synthesis, orby derivation with a chiral auxiliary, where the resultingdiastereomeric mixture is separated and the auxiliary group cleaved toprovided the pure desired enantiomers. Alternatively, where the moleculecontains a basic functional group such as amino, or an acidic functionalgroup such as carboxyl, this resolution may be conveniently performed byfractional crystallization from various solvents, of the salts of thecompounds of formula I with optical active acid or by other methodsknown in the literature, e.g. chiral column chromatography. Resolutionof the final product, an intermediate or a starting material may beperformed by any suitable method known in the art as described by ElielE. L., Wilen S. H. and Mander L. N. (1984) Stereochemistry of OrganicCompounds, Wiley-Interscience.

Many of the heterocyclic compounds of formula I can be prepared usingsynthetic routes well known in the art (Katrizky A. R. and. Rees C. W.(1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).

The product from the reaction can be isolated and purified employingstandard techniques, such as extraction, chromatography,crystallization, distillation, and the like.

The compounds of Formula I may be prepared by general route of synthesisas disclosed in the following methods.

The compounds of formula II-B1 wherein W and G¹ are as described above,B¹ is N and X is C₁-C₆ alkyl may be prepared according to the syntheticsequences illustrated in the Schemes 1-3.

In the turn, an nitrile derivative (for example 4-Fluoro-benzonitrile)is reacted with hydroxylamine under neutral or basic conditions such astriethylamine, diisopropyl-ethylamine, sodium carbonate, sodiumhydroxyde and the like in a suitable solvent (e.g. methyl alcohol, ethylalcohol). The reaction typically proceeds by allowing the reactiontemperature to heat slowly from ambient temperature to a temperaturerange of 70° C. up to 80° C. for a time in the range of about 1 hour upto 48 hours inclusive (see for example Lucca, George V. De; Kim, Ui T.;Liang, Jing; Cordova, Beverly; Klabe, Ronald M.; et al; J. Med. Chem.;EN; 41; 13; 1998; 2411-2423, Lila, Christine; Gloanec, Philippe; Cadet,Laurence; Herve, Yolande; Fournier, Jean; et al.; Synth. Commun.; EN;28; 23; 1998; 4419-4430 and see: Sendzik, Martin; Hui, Hon C.;Tetrahedron Lett.; EN; 44; 2003; 8697-8700 and references therein forreaction under neutral conditions).

The substituted amidoxime derivative (described in the scheme 1) may beconverted to an acyl-amidoxime derivative using the approach outlined inthe Scheme 2. The coupling reaction may be promoted by coupling agentknown in the art of organic synthesis such as EDCI(1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide),DCC(N,N′-Dicyclohexyl-carbodiimide), in a suitable solvent (e.g.tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane)Typically, a co-catalyst such as DMAP (N,N-dimethylaminopyridine) willalso be present in the reaction mixture. The reaction typically proceedsat ambient temperature for a time in the range of about 4 hours up to 12hours to produce the intermediate acyl-amidoxime. The cyclisationreaction may be effected thermally in a temperature range of about 80°C. up to about 150° C. for a time in the range of about 2 hours up to 12hours (see for example Suzuki, Takeshi; Iwaoka, Kiyoshi; Imanishi,Naoki; Nagakura, Yukinori; Miyata, Keiji; et al.; Chem. Pharm. Bull; 47;1; 1999; 120-122). The product from the reaction can be isolated andpurified employing standard techniques, such as extraction,chromatography, crystallization, distillation, and the like.

The scheme 3 illustrates the preparation of compounds of formula II-B1by reacting an alkyne derivative (described in the scheme 2), with asubstituted 5-, 6-heterocyclic containing a N adjacent to the leavinggroup L₁ for example 2-iodo-pyridine. Thus in Scheme 3, L₁ includeshalides such as Cl, Br, I or trifluoromethanesulfonyl andparatoluenesulfonyl. This general route of synthesis has been describedin J. Med. Chem. 2000, 43, 4288-4312.

This palladium catalyzed C—C coupling reaction requires a catalyst suchas PdCl₂(PPh₃)₂, Pd(PPh₃)₄, Pd(OAc)₂ or Pd on carbon in a suitablesolvent like DMF, acetonitrile or benzene. Typically a co-catalyst suchas copper(I) iodide and a base (e.g., triethylamine, diisopropylamine,KOAc . . . ) will also be present in the reaction mixture. The couplingreaction typically proceeds by allowing the reaction temperature to warmslowly from about 0° up to ambient temperature, or heated to atemperature anywhere between 30° C. and 150° C. The reaction mixture isthen maintained at a suitable temperature for a time in the range ofabout 1 up to 24 hours, with about 12 hours typically being sufficient.The product from the reaction can be isolated and purified employingstandard techniques, such as solvent extraction, chromatography,crystallization, distillation, sublimation, and the like.

In another embodiment of the present invention, compounds of formulaII-B1 may be prepared according to the synthetic sequences illustratedin the Schemes 4-5.

A substituted 5-, 6-heterocyclic containing a N adjacent to the leavinggroup L₁ is reacted with an alkyne derivative, in a manner similar tothe procedure presented for Scheme 3. Thus in Scheme 4, L₁ includeshalides such as Cl, Br, I or trifluoromethanesulfonyl andparatoluenesulfonyl. Protecting goups PG₁ are removed using standardmethods to produce a carboxylic acid derivative.

Referring to scheme 5, the di-substituted oxadiazole is prepared asdescribed in scheme 2 from a suitable amidoxime precursor.

The compounds of formula II-C wherein W and B¹, B², B³, and G^(q) are asdescribed above and X is CH₂—NR⁹C(═O) may be prepared according to thesynthetic sequences illustrates in the Schemes 6-7.

In turn, the pentynoic acid may be converted to amide derivative usingthe approach outlined in the Scheme 6. The reaction may be promoted by acoupling agent known in the art of organic synthesis such as EDCI(1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide), DCC(N,N′-Dicyclohexyl-carbodiimide), in a suitable solvent (e.g.tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane)Typically, a co-catalyst such as HOBT (Hydroxybenzotriazole) will alsobe present in the reaction mixture. The reaction typically proceeds atambient temperature for a time in the range of about 4 up to 12 hours.Scheme 7 illustrates the final synthetic step.

The alkyne product from the reaction in Scheme 7 may be prepared usingthe approach outlined in Scheme 3.

Thus, in Scheme 7, L₁ includes halides such as Cl, Br, I ortrifluoromethanesulfonyl and paratoluenesulfonyl.

The compounds of formula II-C wherein W and B¹, B², B³, and G^(q) are asdescribed above and X is

may be prepared according to the synthetic sequences illustrated in theSchemes 8-10.

The substituted propargylic alcohol intermediate from the reaction inScheme 8 may be prepared using the approach outlined in Scheme 3.

The substituted propargylic alcohol derivative may be subsequentlyconverted into the corresponding propargylic halide derivative accordingto the method illustrated in J. Med. Chem., 2000, 48, 8, 1508-1518. Thehalogenation reaction may be promoted by a mixture of halogenatingreagent (for example carbone tetrabromide, PPBr₃, SOCl₂, PCl₅, POCl₃ andthe like) in a suitable solvent (e.g. dichloromethane, tetrahydrofuran,diethylether, toluene). If required a co-reagent, such astriphenylphosphine, will also be present in the reaction mixture. Thereaction is typically allowed to proceed by maintaining at roomtemperature for a time in the range of about 2 hours up to 4 hours.

Thus, in Scheme 8, L₁ includes halides such as Cl, Br, I ortrifluoromethanesulfonyl and paratoluenesulfonyl. And L₂ is halides suchas Cl, Br, I.

The substituted propargylic halide intermediate from the reaction inScheme 8 may be transformed into bis-acetylenic derivatives using theapproach outlined in Scheme 9.

An appropriate aryl- or heteroaryl-alkyl halide derivative is convertedinto the corresponding butynyl derivative according to the methodillustrated in Tetrahedron, 1999, 55, 49, 13907-13926. The alkylationreaction may be promoted by a mixture of trimethyl(prop-1-ynyl)silaneand an organolithium reagent such as n-butyllithium, tButyllithium andthe like which is capable of undergoing metal exchange reaction in asuitable solvent (e.g. tetrahydrofuran, diethylether), at an appropriatetemperature, usually between about −78° C. and 0° C., followed bycondensation of aryl- or heteroaryl-alkyl halide derivatives.

Protecting group trimethylsilyl is removed under basic condition such asNaOH, KOH, K₂CO₃ or nBu₄F and the like according to standard methodsfamiliar to those skilled in the art (J. Org. Chem., 2003, 68, 4,1376-1385). The reaction typically proceeds by allowing the reactiontemperature to warm slowly from ambient temperature to 65° C. for a timebetween 1 h and 24 hours in a suitable solvent (e.g. methyl alcohol,ethyl alcohol, tetrahydrofuran, diethylether).

Thus, in Scheme 9, L₂ includes halides such as Cl, Br, I ortrifluoromethanesulfonyl.

The bis-acetylenic derivative from the reaction in Scheme 9 may beprepared using the approach outlined in Scheme 3.

Thus, in Scheme 10 L₃ includes halides such as Cl, Br, I ortrifluoromethanesulfonyl and paratoluenesulfonyl.

The compounds of formula II-A2 wherein W, G¹, G², G³, G⁴ and G⁵ are asdescribed above, X is CH₂ may be prepared according to the syntheticsequences illustrates in the Schemes 11-14

In accordance with the present invention, imidazopyridine derivativescan be prepared by methods known in the art (A. R. Katrizky A. R. and C.W. Rees (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).

Referring to scheme 11, a substituted aminopyridine derivative D(prepared using synthetic chemistry techniques well known in the art) isreacted with an α-halo-ketoester in a suitable solvent (e.g. EtOH, MeOH,THF, acetone, CH₃CN and the like) at temperature between 50° C. to 90°C. for 5 h to 12 h, to form a substituted imidazopyridine, according tothe method illustrated in J. Med. Chem., 1988, 31, 11, 2221-2227.

The resulting imidazopyridine bearing a carboxylic ester group isconverted into an alcohol by reacting with a reductive agent such asLiAlH₄, BH₃ and the like in a suitable solvent (e.g. THF, diethylether)for a period of time sufficient to proceed to completion, typically fromabout 1 h to 12 h, at ambient temperature being advantageous (see forexample J. Heterocycl. Chem., 1988, 25, 129-137).

The heterocyclic alkyl-alcohol derivative may be subsequently convertedinto the corresponding heterocyclic alkyl-halide derivative according tothe method illustrated in J. Med. Chem., 2000, 48, 8, 1508-1518. Thehalogenation reaction may be promoted by a mixture of halogenatingreagent (for example carbone tetrabromide, PBr₃, SOCl₂, PCl₅, POCl₃ andthe like) in a suitable solvent (e.g. dichloromethane, tetrahydrofuran,diethylether, toluene). If required a co-reagent, such astriphenylphosphine, will also be presented in the reaction mixture. Thereaction is typically allowed to proceed by maintaining at roomtemperature for a time in the range of about 2 hours up to 4 hours.

Thus, in Scheme 11, L₁ includes halides such as Cl, Br, I and PG₁includes Methyl, ethyl, isopropyl, tert-Butyl or benzyl and the like.

In another embodiment of the present invention, depicted in Scheme 12,substituted imidazopyridine alkyl-halide derivatives may be preparedfrom a bis-α-haloketone and a substituted aminopyridine D according tostandard methods familiar to those skilled in the art (J. Heterocyclic.Chem., 1988, 25, 129-137).

The reaction typically proceeds by allowing the reaction temperature toheat slowly from ambient temperature to 65° C. for a time between 1 hand 12 hours in a suitable solvent (e.g. methyl alcohol, ethyl alcohol,tetrahydrofuran, diethylether, acetone and the like). Thus, in Scheme12, L₂ includes halides such as Cl, Br, I.

Thus, in the Scheme 13, a substituted imidazopyridine alkyl-halideintermediate may be transformed into a mono substituted acetylenicderivative using the approach outlined in Scheme 9 to produce thecompound E.

Thus, in Scheme 13, L₂ includes halides such as Cl, Br, I.

The bis-substituted alkyne product from the reaction in Scheme 14 may beprepared using the approach outlined in Scheme 3.

Thus, in Scheme 14 L₃ includes halides such as Cl, Br, I ortrifluoromethanesulfonyl and paratoluenesulfonyl.

In accordance with the present invention, imidazopyridine derivativescan be prepared also using the approach outlined in Scheme 15-17

Thus, in the Scheme 15, an appropriate epoxyde-alkyl halide derivative(e.g., 2-(chloromethyl)oxirane) is converted into the correspondingbutynyl derivative A according to the method illustrated in the Scheme9. The resulting substituted acethylenic intermediate A may besubsequently converted into the intermediate B according to the methodillustrated in S. Hoarau et al., Tetrahedron Asymmetric. 1996, 7,2585-2593 and in Gene W. Holbert et al., Tetrahedron, 1984, 40,1141-1144. The ring opening may be promoted by LiBr or KBr and the likein the presence of acetic acid, in a suitable solvent (e.g. mixturetetrahydrofuran and water), at room temperature for a time in a range ofabout 5 hours up to 12 hours.

In another embodiment of the present invention, depicted in Scheme 15,the intermediate B may be transformed into the correspondingα-halo-ketone C according to the method illustrated in W. Holbert etal., Tetrahedron, 1984, 40, 1141-1144. The oxidation reaction may bepromoted by using oxidative agent such as Jone's reagent (CrO₃/H₂SO₄),TEMPO, PCC and the like by maintaining at room temperature for a time inthe range of about 1 hour up to 2 hours. Thus, in Scheme 15, L₁ L₂include halides such as Cl, Br, I.

Thus, in the Scheme 16, an appropriate α-halo-ketone C is converted intothe corresponding imidazopyridine E according to the cyclisation methodillustrated in the Scheme 11. Protecting group trimethylsilyl is removedunder basic condition such as NaOH, KOH, K₂CO₃ or nBu₄F according to themethod illustrated in the Scheme 9.

The alkyne products from the reaction in Scheme 17 may be prepared usingthe approach outlined in Scheme 3.

Thus, in Scheme 17 L₃ includes halides such as Cl, Br, I ortrifluoromethanesulfonyl and paratoluenesulfonyl.

The compounds of formula II-A1 wherein W, G¹, G², G³, G⁴ and G⁵ are asdescribed above, X is CH₂, B¹, B² is C and B³ is N which may further besubstituted by G^(q) group, may be prepared according to the syntheticsequences illustrate in the Schemes 18-20.

Referring to scheme 18, 1-fluoro-2-nitrobenzene derivative is reactedwith a excess of appropriate substituted amine in suitable solvent (e.g.EtOH, MeOH, THF, acetone, CH₃CN and the like) at temperature between 50°C. to 90° C. for a time in the range of about 5 h up to 12 h, to form aN-substituted-2-nitrobenzenamine according to the method illustrated inTetrahedron Letters, 2002, 43, 7303-7306.

The N-substituted-2-nitrobenzenamine may be subsequently converted intothe corresponding N-substituted-benzene-1,2-diamine derivative accordingto the method known in the art. The reduction reaction may be promotedby 10% Pd/C in a presence of hydrogen source (H₂, HCOONH₄, HCOOH, NaBH₄and the like) or by the presence of metal such as Zinc, Iron and thelike in acidic condition (concentrated HCl, H₂SO₄ or AcOH) in a suitablesolvent (e.g MeOH, AcOH, EtOH). The reaction is typically allowed toproceed by maintaining at room temperature for a time in the range ofabout 2 hours up to 4 hours.

Referring to scheme 19, a N-substituted-benzene-1,2-diamine derivativeis reacted with an α-halo-carboxylic ester or an α-halo-carboxylic acid(X is selected from Cl, Br, I, and PG₁ includes Methyl, ethyl,isopropyl, tert-Butyl or benzyl and the like) to form an substitutedbenzimidazole, according to the method illustrated in J. Heterocyclic.Chem., 1983, 20, 1481-1484.

The reaction typically proceeds by allowing the reaction temperature toheat slowly from ambient temperature to 90° C. in acidic condition(aqueous HCl and the like) for a time between 5 h and 12 hours.

Thus, in the Scheme 20 a substituted imidazopyridine alkyl-halideintermediate may be transformed into a mono substituted acetylenicderivative using the approach outlined in Scheme 9. Thus, in Scheme 20L₂ includes halides such as Cl, Br, I.

The compounds of formula II-B wherein W, Z⁹, Z¹⁰, Z¹¹, Z¹² are asdescribed above and X is C₁-C₃-alkyl may be prepared according to thesynthetic sequences illustrate in Scheme 21-23.

In Scheme 21, a substituted 5-, 6-heterocyclic containing containing anN adjacent to the leaving group L₁ is reacted with acethylenic alcoholunder Sonogashira condition as illustrated in Scheme 3 to produce asubstituted acethylenic alcohol. The resulting alcohol is reacted with aheterocyclic ring containing an acidic NH, under Mitsunobu conditionsaccording to the method illustrated in M. S. Malamas, J. Sredy, I.Gunawan, B. Mihan, D. R. Sawicki, L. Seestaller, D. Sullivan, B. R.Flam, J. Med. Chem. 2000, 43, 995-1010. The Mitsunobu reaction may bepromoted by a reagent such as diethylazodicarboxylate,di-tert-butylazodicarboxylate and the like in the presence oftriphenyphosphine, in a suitable solvent (e.g. tetrahydrofuran), at anappropriate temperature. Subsequent deprotection of the trimethylsilylgroup according to the method illustrated in Scheme 9 and cross couplingafforded a compound of formula II-B.

Thus, in Scheme 21, L₁ may be a good leaving group capable of undergoinga Sonogashira reaction such as Cl, Br, I or trifluoromethanesulfonateand the like.

In another embodiment of the present invention, depicted in Scheme 22, aacetylenic alcohol may be transformed into the corresponding halidederivative, wherein L₁ is Cl, Br or I, according to the methodillustrated in G. C. Crawley, R. I. Dowell, P. N. Edwards, S. J. Foster,R. M. McMillan, J. Med. Chem. 1992, 35, 2600-2609. The halogenationreaction may be promoted by a mixture of halogenating reagents (forexample Br₂, carbone tetrabromide, PBr₃, SOCl₂, PCl₅, POCl₃ and thelike) in a presence of a co-reagent, such as triphenylphosphine, in asuitable solvent (e.g. THF, DCM and the like) and at an appropriatetemperature.

The resulting acetylenic halide may be submitted to substitution asdescribed in Scheme 22 and according to the method illustrated in S. J.Pastine, S. W. Youn, D. Sames, Org. Lett, 2003, 5, 1055-1058. Thesubstitution reaction may be promoted by a nucleophile in the presenceof a base such as K₂CO₃, Cs₂CO₃, NaH and the like in a suitable solvent(e.g. dimethylformamide, acetone, tetrahydrofuran), at an appropriatetemperature. The resulting terminal alkyne is coupled to a substituted5,6-heterocyclic containing nitrogen adjacent to the leaving group L₁ bySonogashira procedure described in Scheme 3.

In another embodiment of the present invention, depicted in Scheme 23, asuitable acetylenic halide bearing an appropriate protectiong group(e.g. trimethylsilyl and the like) may be reacted with a substituted 5-,6-heterocyclic containing containing an N to produce a N-alkylatedheterocyclic derivative as illustrated in Scheme 22. The subsequentdeprotection of the PG₁ according to methods known in the art, followedby Sonogashira coupling affords the compound of formula II-B.

The compounds of formula II-C wherein W, B¹, B², B³ and G^(q) are asdescribed above and X is CH₂—OC(═O) may be prepared according to thesynthetic sequences illustrated in Scheme 24.

The acetylenic alcohol is reacted with an appropriate substituted 5-,6-heterocyclic containing an N adjacent to the leaving group L₁ underSonogashira conditions to produce the substituted the heterocyclicacetylenic alcohol.

In turn, the heterocyclic acetylenic alcohol may be converted to anester derivative using the approach outlined in the Scheme 24. Thereaction may be promoted by coupling agents known in the art of organicsynthesis such as EDCI (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide),DCC(N,N′-Dicyclohexyl-carbodiimide), in a suitable solvent (e.g.tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane).Typically, a co-catalyst such as DMAP (N,N-dimethyl-aminopyridine) willalso be present in the reaction mixture. The reaction typically proceedsat ambient temperature for a time in the range of about 4 up to 12hours.

Thus, in Scheme 24, L₁ may be a good leaving group capable of undergoinga Sonogashira reaction such as Cl, Br, I or trifluoromethanesulfonateand the like.

In the Scheme 25, a compound of formula II-C wherein W, B¹, B², B³ andG^(q) are as described above and X is CH₂—C(═O)—O may be preparedaccording to the synthetic sequences illustrated in Scheme 24.

The compounds of formula II-C wherein W and B¹, B², B³, and G^(q) are asdescribed above and X is CH₂—NHC(═O) may be prepared according to thesynthetic sequences illustrates in the Schemes 26-27.

In turn, the pentynoic acid may be converted to amide derivative usingthe approach outlined in the Scheme 6. The reaction may be promoted bycoupling agent known in the art of organic synthesis such as EDCI(1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide), DCC(N,N′-Dicyclohexyl-carbodiimide), in a suitable solvent (e.g.tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane)Typically, a co-catalyst such as HOBT (Hydroxybenzotriazole) will alsobe present in the reaction mixture. The reaction typically proceeds atambient temperature for a time in the range of about 4 up to 12 hours.

N-protected derivative of the resulting amide may be prepared accordingto the method described in J. Med. Chem., 2000, 43, 3718-3735, by usingfor example BOC₂O in a presence of DMAP in a suitable solvent such asDCM. The reaction typically proceeds at ambient temperature for a timein the range of about 4 up to 12 hours.

Thus, in Scheme 26, PG₁ includes carbamates such as EtO-C(═O),MeO-C(═O), Ph-CH₂—O—C(═O) or tBuOC(═O) and the like.

The resulting acetylenic may be submitted to Sonogshira cross couplingas described in Scheme 27 according to the method outlined in the Scheme3: Removal of the protecting group may be achieved under classicalcondition well known in the art, either under acidic conditions (HCl,H₂SO₄, TFA and the like) or basic condition (NaOH, KOH, NH₃ and thelike) in a suitable solvent such as THF, DCM or MeOH.

Thus, in Scheme 27, L₁ may be a good leaving group capable of undergoinga Sonogashira reaction such as Cl, Br, I or trifluoromethanesulfonateand the like.

The compounds of formula II-C wherein W and B¹, B², B³, and G^(q) are asdescribed above and X is CH₂—NR⁹C(═O)—C₁-C₆-alkyl orCH₂—NR⁹S(═O)₂—C₁-C₆-alkyl may be prepared according to the syntheticsequences illustrated in the Schemes 28-29.

In the Scheme 28, the acetylenic alcohol is reacted with an appropriatesubstituted 5-, 6-heterocyclic containing an N adjacent to the leavinggroup L₁ to produce a substituted heterocyclic alcohol. The alcoholgroup is converted to a better leaving group by using an appropriatesulfonyl chloride (e.g. p-toluenesulphonyl chloride or methansulfonylchloride and the like) in a presense of a base (e.g. NEt₃, DIEA) and ina suitable solvent (DCM, THF and the like). The reaction typicallyproceeds at ambient temperature for a time in the range of about 4 up to12 hours. The intermediate sulfonate is converted into a N-Alkylatedderivative by using an excess of appropriate amine in aqueous solution.The reaction takes place in a range of temperature between 30-50° C. for3 h according to the method described in the J. Org. Chem.; Gao, Y.;Sharpless, K. B.; 53; 17; 1988; 4081-4084.

Thus, in Scheme 28, L₁ may be a good leaving group capable of undergoinga Sonogashira reaction such as Cl, Br, I or trifluoromethanesulfonateand the like, L₂ may be a good leaving group capable of undergoingnucleophilic substitution such as trifluoromethanesulfonate, mesylate orp-toluenesulfonate.

In the Scheme 29, carboxylic acids (L₁ is OH) or their more reactivederivatives (L₁ may be selected from Cl, Br, and the like) is reactedwith an appropriate amine that produce amide according to Scheme 28. Theacylation reaction may be promoted by coupling agents known in the artof organic synthesis such as EDCI(1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide),DCC(N,N′-Dicyclohexyl-carbodiimide) or by polymer-supported couplingagents such as polymer-supported carbodiimide (PS-DCC, ex ArgonautTechnologies), in the presence of a suitable base such as triethylamine,diisopropyl-ethylamine, in a suitable solvent (e.g. tetrahydrofuran,dichloromethane, N,N-dimethylformamide, dioxane). Typically, aco-catalyst such as HOBT (1-Hydroxy-benzotriazole), HOAT(1-Hydroxy-7-azabenzotriazole) and the like may also be present in thereaction mixture. The reaction typically proceeds at ambient temperaturefor a time in the range of about 2 hours up to 12 hours.

Similarly, sulfonyl chloride derivatives (L₁ is OH) may also reactedwith amine derivatives according to the process described in the Scheme29.

The compounds of formula II-A wherein W, Z⁹, Z¹¹, Z¹², Z¹³, Z¹⁴, Z¹⁵,Z¹⁶ and Z¹⁷ are as described above and Z¹⁰ is N may be preparedaccording to the synthetic sequences illustrated in Scheme 30.

A substituted 5-, 6-heterocyclic containing a N adjacent to the leavinggroup L₁ is reacted with but-3-yn-1-ol in a manner similar to theprocedure presented for Scheme 21. Thus, in Scheme 31, L₁ may be a goodleaving group capable of undergoing a Sonogashira reaction such as Cl,Br, I or trifluoromethanesulfonate and the like. The resulting alcoholmay be subsequently converted into a compound of formula II-A accordingto the method illustrated in M. S. Malamas, J. Sredy, I. Gunawan, B.Mihan, D. R. Sawicki, L. Seestaller, D. Sullivan, B. R. Flam, J. Med.Chem. 2000, 43, 995-1010. The Mitsunobu reaction may be promoted by areagent such as diethylazodicarboxylate, di-tert-butylazodicarboxylateand the like in the presence of triphenyphosphine, in a suitable solvent(e.g. dichloromethane), at an appropriate temperature.

In another embodiment of the present invention, compounds of formulaII-A1 wherein W, B¹, B², B³ and G^(q) are as described above may beprepared, as depicted in Scheme 31, from the methyl imidate according tothe method illustrated in M. M. Ponpipom, R. L. Bugianesi, J. C.Robbins, T. W. Doebber, T. Y. Shen, J. Med. Chem. 1981, 24, 1388-1395.The subsequent cyclization may be promoted under mild conditions andfollowed by Sonogashira coupling.

The compounds of formula II-A1 wherein W, B¹, B², B³ and G^(q) are asdescribed above may be prepared according to the following syntheticsequences describe in Scheme 32.

Pentynoic acid is reacted with an aryl- or heteroaryl-amine where B³=Oor S, in the presence of a mixture of triphenylphosphine and CCl₄, in anappropriate solvent, in the presence o a base, followed by Sonogashiracoupling as described in Scheme 3, in order to lead to benzoxazole orbenzothiazole compounds.

The compounds of formula II-A1 wherein W, B¹, B², G^(q) are as describedabove and B³=C═C or N═C may be prepared according to the followingsynthetic sequences illustrated in Scheme 33.

An appropriate 2-methyl-heteroalkyl is coupled to(3-X-prop-1-ynyl)-trimethyl-silane derivative wherein X is a goodleaving group such as Cl or Br and the like, in the presence of a strongbase such as n-butyllithium, lithium diisopropylamine and the like.Trimethylsilyl group is removed under basic condition (e.g. NaOH, KOH,K₂CO₃) or in the presence of fluoride ions (N-tetrabutylammoniumfluoride and the like). The resulting terminal alkyne is coupled to asubstituted 5,6-heterocyclic containing nitrogen adjacent to the leavinggroup L₁ by Sonogashira procedure described in Scheme 3.

The compounds of formula II-A3-a wherein R¹, R², R³, R⁴ and G^(q) are asdescribed above and B¹═C and X═CH₂ may be prepared according to thefollowing synthetic sequences illustrated in Scheme 34.

Trimethylsilanyl-but-3-ynylamine is reacted with substituted1,2-nitrobenzaldehyde in an appropriate solvent such as toluene, ethanol. . . . The resulting imine is reacted in the presence oftriethylphosphite at a certain temperature in order to lead tosubstituted indazoles as in the method illustrated in T. J. Schwan, L.J. Honkomp, C. S. Davis, G. S. Lougheed, J. of Pharm. Sciences 1978, 7,1022-1024. Trimethylsilyl group is removed under basic condition (e.g.NaOH, KOH, K₂CO₃) or in the presence of fluoride ions(N-tetrabutylammonium fluoride and the like). The resulting terminalalkyne is coupled to a substituted pyridine having a leaving group L₁ bySonogashira procedure described in Scheme 3.

The compounds of formula II-A3-a2 wherein R¹, R², R³, R⁴ and G^(q) areas described above may be prepared according to the following syntheticsequences illustrated in Scheme 35.

Benzotriazoles are prepared from substituted benzene-1,2-diamine in thepresence of sodium nitrite and acetic acid as in the method illustratedin J. A. Montgomery, K. Hewson, J. Med. Chem. 1965, 8, 737-740. Thenbut-3-yn-1-ol is reacted with benzotriazoles through Mitsunobu reactionwhich may be promoted by diethylazodicarboxylate,di-tert-butylazodicarboxylate and the like in the presence oftriphenyphosphine, in a suitable solvent (e.g. tetrahydrofuran), at anappropriate temperature. The resulting terminal alkyne is coupled to asubstituted pyridine via Sonogashira procedure described in Scheme 3.

The compounds of formula II-B1 wherein W and G^(q) are as describedabove and X=CH₂ and B¹=C may be prepared according to the syntheticsequences illustrated in Scheme 36.

An acid chloride is reacted with an aminoalcohol under basic conditionssuch as triethylamine in a suitable solvent (e.g. DCM). The resultingamidoalcohol is oxidized in the presence of PCC followed by cyclizationwith POCl₃ and Sonogashira coupling as described in Scheme 3.

The compounds of formula II-C wherein W, X, B¹, B², B³ and G^(q) are asdescribed above may be prepared according to the synthetic sequencesillustrate in Scheme 37.

Propargylation may be promoted by an aryl- or heteroaryl-alkyl halideand propargylmagnesium bromide in the presence of an appropriate solvent(e.g. tetrahydrofuran) at an appropriate temperature, followed bySonogashira coupling as described in Scheme 3.

Pharmacology

Some of the compounds of Formula I have been tested according to thefollowing methods.

mGluR5 Binding Assay

Activity of compounds of the invention was examined following aradioligand binding technique using whole rat brain and tritiated2-methyl-6-(phenylethynyl)-pyridine ([³H]-MPEP) as a ligand followingsimilar methods than those described in F. Gasparini et al. Bioorg. Med.Chem. Lett. 2002, 12, 407-409 and in J. F. Anderson et al. J. Pharmacol.Exp. Ther. 2002, 303, 3, 1044-1051.

Membrane Preparation:

Cortices were dissected out from brains of 200-300 g Sprague-Dawley rats(Charles River Laboratories, L′Arbresle, France). Tissues werehomogenized in 10 volumes (vol/wt) of ice-cold 50 mM Hepes-NaOH (pH 7.4)using a Polytron disrupter (Kinematica AG, Luzern, Switzerland) andcentrifuged for 30 min at 40,000 g. (4° C.). The supernatant wasdiscarded and the pellet washed twice by resuspension in 10 volumes 50mM HEPES-NaOH. Membranes were then collected by centrifugation andwashed before final resuspension in 10 volumes of 20 mM HEPES-NaOH, pH7.4. Protein concentration was determined by the Bradford method(Bio-Rad protein assay, Reinach, Switzerland) with bovine serum albuminas standard.

[³H]-MPEP Binding Experiments:

Membranes were thawed and resuspended in binding buffer containing 20 mMHEPES-NaOH, 3 mM MgCl₂, 3 mM CaCl₂, 100 mM NaCl, pH 7.4. Competitionstudies were carried out by incubating for 1 h at 4° C.: 3 nM [³H]-MPEP(39 Ci/mmol, Tocris, Cookson Ltd, Bristol, U.K.), 50 μg membrane and aconcentration range of 0.003 nM-30 μM of compounds, for a total reactionvolume of 300 μl. The non-specific binding was defined using 30 μM MPEP.Reaction was terminated by rapid filtration over glass-fiber filterplates (Unifilter 96-well GF/B filter plates, Perkin-Elmer,Schwerzenbach, Switzerland) using 4×400 μl ice cold buffer using cellharvester (Filtermate, Perkin-Elmer, Downers Grove, USA). Radioactivitywas determined by liquid scintillation spectrometry using a 96-wellplate reader (TopCount, Perkin-Elmer, Downers Grove, USA).

-   -   Data analysis:

The inhibition curves were generated using the Prism GraphPad program(Graph Pad Software Inc, San Diego, USA). IC₅₀ determinations were madefrom data obtained from 8 point-concentration response curves using anon linear regression analysis.

The table below represents the mean of IC₅₀ obtained from at least threeindependent experiments of selected molecules performed in duplicate.

Example N^(o) IC₅₀ (nM) 1   <500 2 <10 000 3 <10 000 4 <10 000 5 <10 0007   <500 8    <50 9 <10 000 10 <10 000 12 <10 000 13   <500 14 <10 00015   <500 16 <10 000 17 <10 000 18 <10 000 19 <10 000 20 <10 000 21 <10000 22 <10 000 23 <10 000 24 <10 000 25   <500 26 <10 000 28 <10 000 29<10 000 30 <10 000 31    <50 32 <10 000 33    <50 34 <1000 35    <50 36<10 000 37 <10 000 38 <10 000 40 <10 000 41 <10 000 42 <10 000 43 <10000 44 <10 000 45 <10 000 46 <10 000 47 <10 000 48   <500 49 <10 000 50<10 000 51 <10 000 52 <10 000 53 <10 000 54 <10 000 55 <10 000 56 <10000 57 <10 000 58 <10 000 59 <10 000 60 <10 000 61 <10 000 62    <50 63   <50 64    <50 65    <50 66   <500 67 <10 000 68 <10 000 69    <50 70<10 000 71 <10 000 72 <10 000 73 <10 000 74 <10 000 75 <10 000 76 <10000 77    <50 78 <10 000 79 <10 000 80    <50 81    <50 82    <50 83 <10000 84 <10 000 86    <50 87 <10 000 88    <50 89    <50 90    <50 91   <50 92    <50 93    <50 94    <50 95 <10 000 96    <50 97 <10 000 98 <10000 99 <10 000 100 <10 000 101    <50 102 <10 000 103    <50 104    <50105    <50 107   <500 108   <500 109   <500 111 <10 000 112    <50 113<10 000 114    <50 116    <50 117 <10 000 118   <500 120 <10 000 121 <10000 122 <10 000 123 <10 000 124 <10 000 125 <10 000 126   <50 127 <10000 128    <50 129    <50 130    <50 131    <50 132    <50 133 <10 000134 <10 000 135 <10 000 136 <10 000 137    <50 138 <10 000 139    <50140 <10 000 141    <50 142 <10 000 143 <10 000 144 <10 000 145    <50146    <50 147    <50 148 <10 000 149    <50 150    <50 151    <50 152   <50 153 <10 000 154 <10 000 155    <50 156    <50 157 <10 000 159 <10000 160 <10 000 161 <10 000 163    <50 164    <50 165    <50 166   <500167   <500 168 <10 000 169 <10 000 170 <10 000 171 <10 000 172 <10 000174 <10 000 175 <10 000 176 <10 000 177 <10 000 178 <10 000 179   <500180 <10 000 181 <10 000 182 <10 000 183   <500 186 <10 000 187 <10 000188 <10 000 189 <10 000 190   <500 191 <10 000 192   <500 193   <500 194<10 000 197 <10 000 198 <10 000 200 <10 000 202 <10 000 204 <10 000 205<10 000 206 <10 000 207 <10 000 208   <500 209    <50 211 <10 000 212<10 000 213 <10 000 215 <10 000 216 <10 000 217 <10 000 218   <500 219<10 000 220 <10 000 221 <10 000 222 <10 000 223   <500 224    <50 225   <50 226 <10 000 227 <10 000 228    <50 230 <10 000 231 <10 000 232 <10000 233 <10 000 234 <10 000 235    <50 236    <50 241    <50 242 <10 000243 <10 000 244 <10 000 245 <10 000 246 <10 000 247 <10 000 249 <10 000255    <50 256    <50

The compounds of the present invention present a high affinity formGluR5 receptor. As allosteric modulators, they are useful for theproduction of medications, especially for the prevention or treatment ofcentral nervous system disorders as well as other disorders modulated bythis receptor.

The compounds of the invention can be administered either alone, or incombination with other pharmaceutical agents effective in the treatmentof conditions mentioned above.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

The following non-limiting examples are intending to illustrate theinvention. The physical data given for the compounds exemplified isconsistent with the assigned structure of those compounds.

Marble Burying Model of Anxiety

Anxiety models in rodents are used as standard tests to demonstrateanxiolytic-like properties of novel compounds. Mice exhibit a tendencyto bury harmless novel objects when encountered in a test cage. Marbleburying behavior in mice is reduced by compounds which are efficaciousanxiolytics in humans. Thus, marble burying in mice has been used as amodel for the prediction of anxiolytic-like effects of compounds(Millan, M. J. et al., Neuropharmacology, 42:677-684 (2002)).

Selective negative allosteric modulators (allosteric antagonists) of themetabotropic glutamate receptor subtype 5 (mGluR5) have been shownpreviously to reduce marble burying in mice (Spooren, W. P. et al.,Journal of Pharmacology and Experimental Therapeutics, 295:1267-1275(2000)). These results demonstrate that the marble burying test is auseful model for demonstrating the anxiolytic potential of compoundswhich are antagonists of mGluR5. Such compounds may be useful in thetreatment of anxiety and related disorders.

Subjects:

The present studies were performed in accordance with the animal careand use policies of Addex Pharmaceuticals and the EEC directives on theprotection of animals used for experimental and other scientificpurposes (86/609/EEC and subsequent revisions). Male C57BL6/j mice(20-30 g) 7 weeks of age at the time of delivery were group housed in atemperature and humidity controlled facility on a 12 hour light/darkcycle for at least 5 days before use. Mice had access to food and waterad libitum except during marble burying experiments.

Assessment of Marble Burying:

The effect of compounds on marble burying in mice was tested. On the dayof the test, animals were marked on their tails and weighed in aseparate preparation room 1 hour before drug administration. Testcompound or vehicle was administered po 60 minutes prior to the testsession. Marble burying was tested in a separate experimental room. Forthe test, mice were placed individually into clear plastic cages(16×22×14 cm) with 5 cm of sawdust and 10 marbles evenly spaced againstthe walls of the cage. The mice were left undisturbed in the cages for30 minutes. After removal of the mice from the test cages, the number ofmarbles buried was counted. A marble was considered buried if it was ⅔or more covered.

Compound Administration:

Test compounds were dissolved in a solution of 80% 0.1N hydrochloricacid and 20% Tween 80 and adjusted to pH 6 with 1M NaHCO₃. Testcompounds were administered by oral gavage (po) in a volume of 10 ml/kg.Compound-vehicle-treated mice received the equivalent volume of vehiclesolution po in the absence of added compound.

Statistical Analyses:

Statistical analyses were performed using GraphPad PRISM version 4.01statistical software (GraphPad, San Diego, Calif., USA). Data wereanalyzed using one-way analysis of variance (ANOVA) followed byBonferroni-corrected multiple comparisons, or t tests if only 2 groupswere present. The significance level was set at p<0.05.

Effect of Compounds on Marble Burying in Mice

The effect of Example 256 on marble burying in mice is shown in FIG. 1.As can be seen in the figure, Example 256 significantly attenuatedmarble burying in mice (f (3,36)=5.04, n=10/group). Bonferroni-correctedmultiple comparisons revealed a statistically significant differenceshowing that mice treated with 30 mg/kg po of Example 256 buried fewermarbles than vehicle-treated mice (t=3.686, p<0.01). These resultsdemonstrate that Example 256 attenuates marble burying in mice andsuggests that compounds of Formula II-A2-a2 may be useful in thetreatment of anxiety.

The effect of Example 255 on marble burying in mice is shown in FIG. 2.As can be seen in the figure, mice treated with 50 mg/kg po of Example255 buried significantly fewer marbles than vehicle-treated mice (t (1,18)=3.92, n=10/group). These results demonstrate that Example 255attenuates marble burying in mice and suggests that compounds of theinvention may be useful in the treatment of anxiety.

Vogel Conflict Drinking Model of Anxiety in Rats

Anxiety models in rodents are used as standard tests to demonstrateanxiolytic-like properties of novel compounds. The Vogel conflictdrinking model involves the conflict between thirst and receiving mildshocks for drinking water (punished drinking). Water-deprived rats areplaced in a chamber and are periodically shocked for drinking water. Theshocks suppress drinking and anxiolytics reverse this shock-inducedsuppression of drinking. The Vogel conflict drinking model was firstproposed as a screening model for anxiolytics (Vogel, J. R. et al.,Psychopharmacologia (Berl.), 21:1-7 (1971)) and is widely accepted as arobust model for testing the anxiolytic-like properties of compounds(Millan, M. J. and Brocco M., European Journal of Pharmacology,463:67-96 (2003)).

Selective negative allosteric modulators (allosteric antagonists) of themetabotropic glutamate receptor subtype 5 (mGluR5) have been shown toincrease punished drinking in rats (Varty, G. B. et al.,Psychopharmacology (Berl.) 179:207-217. (2005)). These resultsdemonstrate that the Vogel conflict drinking test is a useful model fordemonstrating the anxiolytic potential of compounds which areantagonists of mGluR5. Such compounds may be useful in the treatment ofanxiety and related disorders.

Subjects:

The present studies were performed in accordance with the animal careand use policies of Addex Pharmaceuticals and the EEC directives on theprotection of animals used for experimental and other scientificpurposes (86/609/EEC and subsequent revisions). Male Sprague-Dawley rats(350 g) 7-9 weeks of age at the time of testing were group housed in atemperature and humidity controlled facility on a 12 hour light/darkcycle for at least 5 days before use. Rats had access to food ad libitumexcept during Vogel conflict drinking model experiments. Rats had accessto water ad libitum until 48 hours prior to the test session.

Assessment of Vogel Conflict Drinking:

The effect of compounds on drinking in the Vogel conflict drinking modelin rats was tested. Test chambers are housed in sound-attenuating boxesand each chamber contains a stainless steel drinking spout and a steelgrid floor (MedAssociates, Georgia, Vt., USA). Forty-eight hours priorto the test session, rats were habituated to the test chambers for 10minutes. Water was removed from the rats immediately after thehabituation session. Twenty-four hours before the test session, ratswere again placed into the test chambers and allowed to drink for 4minutes. Rats were then allowed 1 hour of access to water and then waterwas removed. On the test day, rats were brought to the test room atleast 30 minutes before the test session. Rats were placed individuallyinto the test chamber for a 5 minute session. Rats received a shockevery 20^(th) lick on the drinking spout. The number of punished drinkswas counted automatically by the computer interface. The number ofpunished drinks was compared between treatment groups. An increase inthe number of punished drinks in rats treated with a compound isinterpreted as an anxiolytic-like effect.

Compound Administration:

Test compounds (Examples 256 and 130) were dissolved either in asolution of 80% 0.1N hydrochloric acid, 20% Tween 80 and adjusted to pH6 with 1M NaHCO₃ (Example 256) or a 7.5% Arabic gum/H₂O solution(Example 130). Test compounds were administered by oral gavage (po) in avolume of 3 ml/kg. Compound-vehicle-treated rats received the equivalentvolume of vehicle solution po in the absence of added compound.

Statistical Analyses:

Statistical analyses were performed using GraphPad PRISM version 4.01statistical software (GraphPad, San Diego, Calif., USA). Data wereanalyzed using one-way analysis of variance (ANOVA) followed byBonferroni multiple comparisons. The significance level was set atp<0.05.

Effect of Compounds on Drinking in the Vogel Conflict Drinking Model inRats

The effect of Example 256 on punished drinking in the Vogel conflictdrinking test is shown in FIG. 3. As can be seen in the figure, Example256 significantly increased punished drinking in rats (f (2,26)=6.845,n=9-10/group). Bonferroni-corrected multiple comparisons revealed astatistically significant difference showing that rats treated with 10mg/kg po of Example 256 accepted significantly more shocks thanvehicle-treated rats (t=3.585, p<0.01).

Example 130 also induced an anxiolytic effect in the Vogel conflictdrinking test (FIG. 4). Specifically, rats that received 30 mg/kg ofExample 130 took significantly more punished licks than vehicle injectedcontrols (t(1, 17)=2.593, n=9-10/group). These data indicate thatExample 256 and 130 are anxiolytic in the Vogel conflict drinking test.

Summary of Behavioral Results

The results presented above demonstrate that Examples 255, 256, and 130are effective in specific models of anxiety in rodents. These resultssuggest that compounds of the invention may be useful in the treatmentof anxiety disorders and related disorders and diseases of the centralnervous system.

EXAMPLES

Unless otherwise noted, all starting materials were obtained fromcommercial suppliers and used without further purification.

Specifically, the following abbreviations may be used in the examplesand throughout the specification.

% (percent) M (molar) AcOEt (ethyl acetate) mbar (millibar) (BOC)₂O(Di-tert-butyl dicarbonate) MeOH (methanol) n-BuLi (n-butyllithium) mg(milligrams) ° C. (Celsius degrees) MgSO₄ (magnesium sulphate) CDCl₃(deuterated chloroform) MHz (megahertz) CHCl₃ (chloroform) min (minutes)CuI (copper iodide) μL(microliters) DAST (diethylaminosulfurtrifluoride) mL (milliliters) DCM (dichloromethane) mmol (millimoles)dec. (decomposition) Mp (melting point) DIEA (diisopropyl ethyl amine) N(normal) DMAP (N,N-dimethylaminopyridine) N₂ (nitrogen) DMF(dimethylformamide) NaCl (Sodium chloride) DMSO (dimethyl sulfoxide)NaHCO₃ (sodium hydrogenocarbonate) EDCI•HCl (1-3(Dimethylaminopropyl)-3-NaOH (sodium hydroxide) ethylcarbodiimide, hydrochloride) Et₂O (diethylether) Na₂SO₄ (sodium sulphate) g (grams) NH₄Cl (ammonium chloride) h(hour) NH₄OH (ammonium hydroxide) ¹H (proton) NMR (Nuclear MagneticReasonance) HCl (hydrochloric acid) PdCl₂(PPh₃)₂(Bis(triphenylphosphine) palladium (II) dichloride HOBT(1-hydroxybenzotriazole) Pd(PPh₃)₄(tetrakis(triphenylphosphine)palladium(0) HPLC (High Pressure LiquidChromatography) P₂O₅ (phosphorus pentoxide) H₂SO₄ (Sulfuric acid) POCl₃(phosphorus oxychloride) Hz (Hertz) r.t. (room temperature) K₂CO₃(potassium carbonate) THF (tetrahydrofuran) KI (potassium iodide) TLC(tin chromatography layer) LCMS (Liquid Chromatography Mass Spectrum) RT(Retention Time) LiAlH₄ (lithium aluminium hydride)

All references to brine refer to a saturated aqueous solution of NaCl.Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions are conducted not under an inertatmosphere at room temperature unless otherwise noted.

The microwave oven used is an apparatus from Biotage (Optimizer™)equipped with an internal probe that monitors reaction temperature andpressure, and maintains the desired temperature by computer control.

¹H NMR spectra were recorded on a Brucker 500 MHz. Chemical shifts areexpressed in parts of million (ppm, 8 units). Coupling constants are inunits of hertz (Hz). Splitting patterns describe apparent multiplicitiesand are designated as s (singulet), d (doublet), t (triplet), q(quadruplet), quint (quintuplet), m (multiplet).

LCMS were recorded on a Waters Micromass ZQ 2996 system by the followingconditions. Column 3.0*50 mm stainless steel packed with 5 μm XTerra RPC-18; flow rate 1 ml/min; mobile phase: A phase=0.1% formic acid inwater, B phase=0.07% formic acid in acetonitrile. 0-0.5 min (A: 95%, B:5%), 0.5-6.0 min (A: 0%, B: 100%), 6.0-6.5 min (A: 95%, B: 5%), 6.5-7min (A: 95%, B: 5%); UV detection Diode Array: 200-400 nm; Injectionvolume: 3 μl.

All mass spectra were taken under electrospray ionisation (ESI) methods.

Most of the reaction were monitored by thin-layer chromatography on 0.25mm Macherey-Nagel silica gel plates (60E-2254), visualized with UVlight. Flash column chromatography was performed on silica gel (220-440mesh, Fluka). Melting point determination was performed on a Buchi B-540apparatus.

Example 1 2-Methyl-(4-(4-phenyl)but-1-ynyl)thiazole

To a solution of CuI (45 mg, 24 mol) in triethylamine (3 mL) were added4-bromo-2-methylthiazole (85 mg, 0.48 mmol) and (PPh₃)₂PdCl₂ (17 mg, 24mol). The reaction mixture was cooled to 0° C. and 1-(but-3-ynyl)benzene(67 μl, 0.48 mmol) was added. The reaction mixture was allowed to warmto room temperature and then heated under reflux for 3 days.Triethylamine was evaporated, water was added and the aqueous phase wasextracted twice with DCM. The organic phase was washed with NH₄OHsolution, dried over Na₂SO₄, filtered and concentrated. The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 9:1) toyield 25 mg (0.1 mmol, 23%) of 2-methyl-(4-(4-phenyl)but-1-ynyl)thiazoleas a yellow oil.

LCMS (RT): 4.87 min; MS (ES+) gave m/z: 229.2.

Example 22-(4-(3-(2-Ethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2(A)3-Chloro-N′-hydroxy-2-methylbenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-ethylbenzonitrile (0.92 g, 7 mmol)afforded 1.12 g of 2-ethyl-N′-hydroxybenzamidine (Yield: 97%) as whitepowder (M.P.=54-55° C.).

Rf (DCM/MeOH: 97/3): 0.20

LCMS (RT): 0.81 min; MS (ES+) gave m/z: 165.0

2(B) 5-(But-3-ynyl)-3-(2-ethylphenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 3-chloro-N′-hydroxy-2-methylbenzamidine(560 mg, 3.4 mmol) afforded 343 mg of5-(but-3-ynyl)-3-(2-ethylphenyl)-1,2,4-oxadiazole (Yield: 44%) as yellowoil.

Rf (DCM/MeOH: 99/1): 0.75

LCMS (RT): 4.86 min; MS (ES+) not detected

2(C) 2-(4-(3-(2-Ethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(2-ethylphenyl)-1,2,4-oxadiazole (342 mg, 1.51 mmol)afforded 213 mg of2-(4-(3-(2-ethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl) pyridine (Yield46%) as yellow oil.

LCMS (RT): 4.71 min; MS (ES+) gave m/z: 304.0

¹NMR (CDCl₃), δ (ppm): 8.62 (s, H), 7.92 (d, H), 7.63 (t, H), 7.45-7.20(m, 5H), 3.33 (t, 2H), 3.07 (t, 2H), 3.00 (q, 2H), 1.23 (t, 3H).

Example 3 2-(4-(Pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione 3(A)4-(Pyridin-2-yl)but-3-yn-1-ol

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (10.3 g, 65.1 mmol) and but-3-yn-1-ol(5.08 mL, 67.1 mmol). Reaction time: 14 hours. The crude residue waspurified by flash chromatography (DCM/AcOEt 3:7 to 1:9) to yield 6.10 g(41.4 mmol, 64%) of 4-(pyridin-2-yl)but-3-yn-1-ol as a brown oil.

3(B) 2-(4-(Pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione

4-(Pyridin-2-yl)but-3-yn-1-ol (96 mg, 0.65 mmol), isoindoline-1,3-dione(140 mg, 0.97 mmol) and triphenylphosphine polymer bound 3 mmol/g (340mg, 1.02 mmol) were dissolved in DCM (2 mL) and cooled to 0° C.Di-tert-butylazodicarboxylate (226 mg, 0.96 mmol) dissolved in DCM (0.5mL) was added dropwise over 30 min. to the reaction mixture followed byTHF (0.5 mL) and the reaction mixture was stirred for 16 h at roomtemperature. After filtration through celite, the organic phase waswashed with a solution of NH₄OH, brine, dried over Na₂SO₄, filtered andconcentrated. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 3:7) to yield 130 mg (0.47 mmol, 73%) of2-(4-(pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as an orange solid.

LCMS (RT): 3.08 min; MS (ES+) gave m/z: 277.2.

¹H-NMR (CDCl₃), δ (ppm): 2.91 (t, J=7.0, 2H), 4.02 (t, J=7.0, 2H),7.34-7.43 (m, 1H), 7.47-7.55 (m, 1H), 7.73 (dd, J=3.0 and 5.5, 2H),7.80-7.85 (m, 1H), 7.86 (dd, J=3.0 and 5.5, 2H), 8.56-8.61 (m, 1H).

Example 4 2-(4-(Pyridin-2-yl)but-3-ynyl)phthalazin-1(2H)-one

The title compound was prepared in accordance with the general method ofExample 3(B), from 4-(pyridin-2-yl)but-3-yn-1-ol (102 mg, 0.69 mmol,Example 3(A)) and phthalazin-1(2H)-one (152 mg, 1.04 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1 to 97:3)followed by bulb-to-bulb distillation (100° C., 0.1 mbar) to yield 22 mg(79 mmol, 11%) of 2-(4-(pyridin-2-yl)but-3-ynyl)phthalazin-1(2H)-one asa brown solid.

LCMS (RT): 2.70 min; MS (ES+) gave m/z: 276.2.

¹H-NMR (CDCl₃), δ (ppm): 3.18 (t, J=7.0, 2H), 4.59 (t, J=7.0, 2H),7.72-7.85 (5H), 8.23 (s, 1H), 8.23-8.28 (m, 1H), 8.43 (d, J=7.5, 1H),8.72 (d, J=6.0, 1H).

Example 5 2-(4-Phenylbut-1-ynyl)quinoline

The title compound was prepared in accordance with the general method ofExample 1, from 2-chloroquinoline (300 mg, 1.83 mmol) and1-(but-3-ynyl)benzene (200 mg, 1.54 mmol). The crude residue waspurified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 148mg (0.57 mmol, 37%) of 2-(4-phenylbut-1-ynyl)quinoline as an orange oil.

LCMS (RT): 4.51 min; MS (ES+) gave m/z: 258.2.

¹H-NMR (CDCl₃), δ (ppm): 2.80 (t, J=7.5, 2H), 3.02 (t, J=7.5, 2H),7.21-7.25 (m, 1H), 7.27-7.35 (4H), 7.43 (d, J=8.5, 1H), 7.52-7.56 (m,1H), 7.70-7.74 (m, 1H), 7.79 (d, J=8.0, 1H), 8.09-8.20 (2H).

Example 6 2-(4-Phenylbut-1-ynyl)pyrimidine

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyrimidine (290 mg, 1.82 mmol) and1-(but-3-ynyl)benzene (200 mg, 1.54 mmol). The crude residue waspurified by flash chromatography (cyclohexane/AcOEt 85:15) to yield 275mg (1.32 mmol, 86%) of 2-(4-phenylbut-1-ynyl)pyrimidine as a yellow oil.

LCMS (RT): 3.51 min; MS (ES+) gave m/z: 209.2.

¹H-NMR (CDCl₃), δ (ppm): 2.76 (t, J=7.5, 2H), 3.00 (t, J=7.5, 2H),7.20-7.24 (2H), 7.25-7.28 (2H), 7.29-7.33 (2H), 8.70 (d, J=5.0, 2H).

Example 7 2-(4-Phenylbut-1-ynyl)benzo[d]oxazole

To a solution of CuI (15 mg, 81 mmol) in triethylamine (3 mL) were added2-chlorobenzo[d]oxazole (250 mg, 1.63 mmol), (PPh₃)₂PdCl₂ (57 mg, 81μmol), triphenylphosphine polymer bound 3 mmol/g (98 mg, 293 μmol) and asolution of 1-(but-3-ynyl)benzene (250 mg, 1.92 mmol) in DMF (0.5 mL).The reaction mixture was stirred for 25 min. at 120° C. in the microwavecavity. The reaction was quenched as described in Example 1. The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 95:5) toyield 163 mg (0.66 mmol, 40%) of 2-(4-phenylbut-1-ynyl)benzo[d]oxazoleas an orange oil.

LCMS (RT): 4.84 min; MS (ES+) gave m/z: 248.1.

¹H-NMR (CDCl₃), δ (ppm): 2.81 (d, J=7.5, 2H), 3.00 (d, J=7.5, 2H),7.21-7.26 (m, 1H), 7.26-7.29 (2H), 7.31-7.40 (4H), 7.48-7.51 (m, 1H),7.70-7.72 (m, 1H).

Example 8 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole hydrochloride8(A) 2-(But-3-ynyl)benzo[d]oxazole

A solution of triphenylphosphine (16.0 g, 61.2 mmol) in a mixture ofacetonitrile/pyridine 1:1 (30 mL) was added dropwise over 2 hours to asolution of pent-4-ynoic acid (2.00 g, 20.4 mmol), 2-aminophenol (2.31g, 21.0 mmol), Et₃N (8.50 mL, 61.2 mmol) and CCl₄ (7.87 mL, 81.6 mmol)in acetonitrile/pyridine 1:1 (20 mL). The reaction mixture was stirredfor 2 days at room temperature and the solvent was evaporated. Theresidue was dissolved in DCM and washed with a saturated solution ofNH₄OH. The aqueous phase was extracted twice with DCM. The resultingorganic phase was dried over MgSO₄, filtered and evaporated. The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 9:1) toyield 1.37 g (8.03 mmol, 39%) of 2-(but-3-ynyl)benzo[d]oxazole as a redoil.

8(B) 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (746 mg, 4.67 mmol) and2-(but-3-ynyl)benzo[d]oxazole (800 mg, 4.67 mmol). Reaction time: 3hours. The crude residue was dissolved in DCM,syn-2-pyridinecarboxaldoxime (684 mg, 5.60 mmol) was added and thereaction mixture was stirred overnight. The solvent was evaporated andthe resulting crude product was purified by flash chromatography(DCM/MeOH 99:1) to yield 923 mg (3.72 mmol, 79%) of2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a yellow solid.

8(C) 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole hydrochloride

A solution of HCl in dioxane (4.65 mL, 0.8 M, 3.72 mmol) was added to asolution of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole (923 mg, 3.72mmol) in dioxane (50 mL). The resulting suspension was cooled at 0° C.for 1 hour and was filtered. The precipitate was washed twice withdioxane and dried under vacuum to yield2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole hydrochloride (830 mg,2.91 mmol, 78%) as a white solid (M.P.=143.5-145° C.).

LCMS (RT): 3.29 min; MS (ES+) gave m/z: 249.1.

Rf (DCM/MeOH 98:2)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 3.25 (t, J=7.4, 2H), 3.43 (t, J=7.4, 2H),7.32-7.38 (2H), 7.52-7.56 (m, 1H), 7.69-7.73 (m, 1H), 7.74-7.80 (2H),8.24-8.28 (m, 1H), 8.73 (d, J=6.0, 1H).

Example 92-(4-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 9(A)Ethyl pent-4-ynoate

In analogy to the method as described in Tetrahedron., 2000, 56,5735-5742, a mixture of the 4-pentynoic acid (10 g, 102 mmol) and H₂SO₄98% (0.338 mL, 6.12 mmol) in ethanol (113 mL) was heated at 50° C.overnight. The reaction mixture was concentrated and the crude productwas dissolved in ethyl acetate, washed with NaHCO₃ 1M and water. Thesolvent was removed under reduced pressure to afford 9.04 g of ethylpent-4-ynoate (Yield: 70%) as a colorless oil.

9(B) Ethyl 5-(pyridin-2-yl)pent-4-ynoate

In a dry reaction tube containing in suspension copper iodide (60 mg,0.315 mmol) and triethylamine (17.70 mL, 126 mmol), were added2-iodopyridine (1.29 g, 6.30 mmol) and the Pd(PPh₃)₂Cl₂ (202 mg, 0.315mmol). A yellow suspension is obtained and after a few minutes ofstirring at room temperature, was added ethyl pent-4-ynoate (790 mg,6.30 mmol) in solution in 2 mL of triethylamine. Immediately the colorof the reaction turns to black. The mixture was stirred at roomtemperature for 30 min and then at 80° C. for 20 h. Triethylamine wasconcentrated under reduce pressure and the residue was dissolved in DCM.The organic layer was washed with saturated NH₄Cl, water and brine. Thesolvent was removed under reduced pressure and the crude product waspurified by flash chromatography system (prepacked silicagel column 25g, DCM/MeOH:98/2 as eluent) to afford 1.17 g of ethyl5-(pyridin-2-yl)pent-4-ynoate (Yield: 78%) as brownish oil.

9(C) 5-(Pyridin-2-yl)pent-4-ynoic acid

To a aqueous solution of 1M NaOH (9.9 mL) heated at 50° C., was addedslowly a solution of ethyl 5-(pyridin-2-yl)pent-4-ynoate (2 g, 9.90mmol) in 3 mL of ethanol. The reaction mixture was stirred 1 h 30 at 50°C. and cooled to room temperature. An aqueous 1N HCl (9.9 mL, 9.90 mmol)was then added and the solvent was removed under pressure to afford 2.3g of 5-(pyridin-2-yl)pent-4-ynoic acid (Yield: 99%) as a brown solidwhich can be used without further purification.

9(D) 2-(4-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

A mixture of commercially available 4-fluoro-N′-hydroxybenzamidine (220mg, 1.4 mmol), 5-(pyridin-2-yl)pent-4-ynoic acid (330 mg, 1.4 mmol),HOBT (210 mg, 1.4 mmol) and EDCI.HCl (400 mg, 2.1 mmol) in dioxane (4.5mL) was stirred at R.T for 7H, The reaction mixture was then heated at100° C. for 36 h. The solvent was removed under reduced pressure and theresidue was dissolved in DCM. The organic layer was washed with water,1N NaOH and water. The organic layer was dried over Na₂SO₄, filtred andevaporated. Purification by flash chromatography (prepacked 10 gsilicagel column, DCM/MeOH: 99/1 as eluent) to afford 103 mg of2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 25%) as a yellow oil.

LCMS (RT): 3.99 min; MS (ES+) gave m/z: 294.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 8.10 (m, 2H), 7.68 (t, H), 7.41 (d,H), 7.27 (d, H), 7.21-7.14 (m, 2H), 3.32 (t, 2H), 3.07 (t, 2H).

Example 10 2-(4-(3-Phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the protocol described in Example 9(D), the conversion ofcommercially available N′-hydroxybenzamidine (190 mg, 1.4 mmol) afforded59 mg of 2-(4-(3-phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 15%) as yellow oil.

LCMS (RT): 3.83 min; MS (ES+) gave m/z: 276.0

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 8.09 (m, H), 7.70 (t, H), 7.54-7.46(m, 3H), 7.42 (d, H), 7.30-7.25 (m, 2H), 3.33 (t, 2H), 3.09 (t, 2H).

Example 11 2-Methyl-4-(4-phenylbut-1-ynyl)-1H-imidazole 11(A) Ethyl4-iodo-2-methyl-1H-imidazole-1-carboxylate

In general, modifications were made from the procedure given in J. Org.Chem., 1999, 64, 23, 8608-8615. A solution of commercially available4-iodo-2-methyl-1H-imidazole (520 mg, 2.5 mmol) in THF (8.3 mL),containing DIEA (1.07 mL, 6.25 mmol) and DMAP (150 mg, 1.30 mmol), wascooled in a ice bath at 0° C. A solution of ethyl chloroformate (678 mg,6.25 mmol) in THF (2.5 mL) was slowly added over a period of 20 min tothe reaction mixture. The reaction mixture was heated at 50° C. for 48 hand the solvent was removed under reduced pressure. The residue wasdissolved in DCM and the organic layer was washed with brine, water,dried over MgSO₄, filtered and evaporated. Purification by flashchromatography (prepacked 10 g silicagel column, DCM/MeOH:97/3 aseluent) to afford 660 mg of ethyl4-iodo-2-methyl-1H-imidazole-1-carboxylate (Yield: 94%) as a colorlessoil.

11(B) Ethyl 2-methyl-4-(4-phenylbut-1-ynyl)-1H-imidazole-1-carboxylate

In a dry reaction tube containing in suspension iodide copper (20 mg,0.1 mmol) and triethylamine (5.81 mL, 41.40 mmol), were added ethyl4-iodo-2-methyl-1H-imidazole-1-carboxylate (580 mg, 2.07 mmol) and thePd(PPh₃)₂Cl₂ (66 mg, 0.1 mmol). A yellow suspension is obtained andafter a few minutes stirred at room temperature was added thecommercially available 4-phenyl-1-butyn (269 mg, 2.07 mmol) intriethylamine (0.5 mL). Immediately the color of the reaction turns toblack.

The mixture was stirred at room temperature for 30 min and then at 80°C. for 20 h. Triethylamine was concentrated under reduce pressure andthe residue was dissolved in DCM. The organic layer was washed withsaturated NH₄Cl, water and brine, dried (MgSO₄) and concentrated.Purification by flash chromatography (prepacked 25 g silicagel column,DCM/MeOH: 99/1 as eluent) to afford 410 mg of ethyl2-methyl-4-(4-phenylbut-1-ynyl)-1H-imidazole-1-carboxylate (Yield: 70%)as a brown oil.

Rf (DCM/MeOH: 99/1)=0.3

LCMS (RT): 4.39 min; MS (ES+) gave m/z: 283.1

11(C) 2-Methyl-4-(4-phenylbut-1-ynyl)-1H-imidazole

0.45 mL of NaOH 2.0 N was added dropwise to a solution ethyl2-methyl-4-(4-phenylbut-1-ynyl)-1H-imidazole-1-carboxylate (250 mg, 0.9mmol) in ethanol (4.5 mL) and the mixture was heated at 80° C.overnight. Ethanol was concentrated under reduced pressure, To the crudeproducr was added water and the aqueous layer was extracted with DCM.The recombined organics layers were washed with brine, dried over MgSO₄,filtered and concentrated to afford 163 mg of2-methyl-4-(4-phenylbut-1-ynyl)-1-imidazole (Yield: 86%) as a beigesolid (M.P.=124-126° C.).

Rf (DCM/MeOH: 95/5)=0.3

LCMS (RT): 0.64-2.41 min; MS (ES+) gave m/z: 211.2

¹NMR (CDCl₃), δ (ppm): 7.32-7.19 (m, 6H), 3.80 (s, NH), 2.89 (m, 2H),2.67 (m 2H), 2.43 (s, 3H).

Example 12 N-Methyl-N-phenyl-5-(pyridin-2-yl)pent-4-ynamide 12(A)N-methyl-N-phenylpent-4-ynamide

To a solution of N-methylbenzenamine (110 mg, 1.02 mmol) in DCM (3 mL)was successively added at R.T. 4-pentynoic acid (100 mg, 1.02 mmol),HOBT (171 mg, 1.12 mmol) and EDCI.HCl (293 mg, 1.53 mmol). The reactionwas stirred at R.T. overnight. The reaction was quenched with water. Theorganic layer was separated and washed with 1M NaHCO₃ and water. Thesolvent was removed under reduced pressure to afford 150 mgN-methyl-N-phenylpent-4-ynamide (Yield: 78%) as an orange oil which cnbe used without further purification.

LCMS (RT): 3.26 min; MS (ES+) gave m/z: 188.1

12(B) N-Methyl-N-phenyl-5-(pyridin-2-yl)pent-4-ynamide

According to the protocol described in Example 74(E), the conversion ofN-methyl-N-phenylpent-4-ynamide (150 mg, 0.80 mmol) afforded 130 mg ofN-methyl-N-phenyl-5-(pyridin-2-yl)pent-4-ynamide (Yield: 61%) as orangesolid (M.P.=68-71° C.). Purification by flash chromatography (prepacked25 g silicagel column, DCM/MeOH:95/5 as eluent)

Rf (DCM/MeOH: 95/5)=0.20

LCMS (RT): 2.89 min; MS (ES+) gave m/z: 265.1

¹NMR (CDCl₃), δ (ppm): 8.55 (s, H), 7.73 (t, H), 7.48-7.40 (m, 3H), 7.36(t, H), 7.29 (t, H), 7.25-7.20 (m, 2H), 3.30 (s, 3H), 2.77 (t, 2H), 2.45(t, 2H).

Example 13 N-(4-Fluorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide13(A) N-(4-fluorophenyl)-N-methylpent-4-ynamide

According to the protocol described in Example 12(A), the conversion of4-fluoro-N-methylbenzenamine (127 mg, 0.52 mmol) afforded 180 mg ofN-(4-fluorophenyl)-N-methylpent-4-ynamide (Yield: 91%) as orange oil.

LCMS (RT): 3.38 min; MS (ES+) gave m/z: 206.1

13(B) N-(4-Fluorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide

According to the protocol described in Example 74(E), the conversion ofN-(4-fluorophenyl)-N-methylpent-4-ynamide (170 mg, 0.83 mmol) afforded157 mg of N-(4-fluorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide(Yield: 67%) as orange oil. Purification by Flash chromatography(prepacked 25 g silicagel column, DCM/MeOH: 95/5 as eluent)

Rf (DCM/MeOH: 95/5)=0.23

LCMS (RT): 3.06 min; MS (ES+) gave m/z: 283.1

¹NMR (CDCl₃), δ (ppm): 8.55 (s, H), 7.65 (t, H), 7.47 (d, H), 7.24-7.18(m, 3H), 7.15-7.08 (m, 2H), 3.26 (s, 3H), 2.75 (t, 2H), 2.41 (t, 2H).

Example 14 2-(4-(2-Phenylthiazol-4-yl)but-1-ynyl)pyridine 14(A)4-(Bromomethyl)-2-phenylthiazole

Bromine (177 mg, 1.1 mmol) was added directly into a solution oftriphenylphosphine (288 mg, 1.1 mmol) in DCM (2 mL) to give a kind ofwhite precipitate. The temperature was cooled to −6° C. A solution ofcommercially available (2-phenylthiazol-4-yl)methanol (200 mg, 1.04mmol) in DCM (1 mL) was added dropwise. The resulting mixture wasmaintained at −6° C. for 15 min and then warmed to room temperature for1 h. A white precipitate was formed. The solution was filtered and thewhite precipitate was washed with DCM. The white precipitate wascollected and dissolved in NaHCO₃ 0.5M After 30 min of stirring, theaqueous layer was extracted with DCM and the organic phase was washedwith water, dried over MgSO₄, filtered and evaporated to afford 248 mgof 4-(bromomethyl)-2-phenylthiazole (Yield 71%) as a yellow oil.

LCMS (RT): 4.46 min; MS (ES+): no ionisation

14(B) 4-(4-(Trimethylsilyl)but-3-ynyl)-2-phenylthiazole

According to the protocol described in Example 74(C), the conversion of4-(bromomethyl)-2-phenylthiazole (185 mg, 0.73 mmol) afforded 191 mg of4-(4-(trimethylsilyl)but-3-ynyl)-2-phenylthiazole (Yield: 92%) as yellowoil.

LCMS (RT): 5.56 min; MS (ES+) gave m/z: 286.1

14(C) 4-(But-3-ynyl)-2-phenylthiazole

According to the protocol described in Example 74(D), the conversion of4-(4-(trimethylsilyl)but-3-ynyl)-2-phenylthiazole (191 mg, 0.67 mmol)afforded 111 mg of 4-(but-3-ynyl)-2-phenylthiazole (Yield: 77%) asyellow oil.

LCMS (RT): 4.53 min; MS (ES+) gave m/z: 214.1

14(D) 2-(4-(2-Phenylthiazol-4-yl)but-1-ynyl)pyridine

According to the protocol described in Example 74(E), the conversion of4-(but-3-ynyl)-2-phenylthiazole (111 mg, 0.52 mmol) afforded 88 mg of2-(4-(2-phenylthiazol-4-yl)but-1-ynyl)pyridine (Yield: 58%) as brownoil. Purification by flash chromatography (prepacked 10 g silicagelcolumn, DCM 100% as eluent).

Rf (Cyclohexane/AcOEt: 60/40)=0.23

LCMS (RT): 4.11 min; MS (ES+) gave m/z: 291.1

¹NMR (CDCl₃), δ (ppm): 8.61 (s, H), 7.98-7.93 (m, 2H), 7.76 (t, H),7.48-7.40 (m, 4H), 7.33 (m, H), 7.18 (m, H), 3.20 (t, 2H), 2.98 (t, 2H).

Example 15 2-(4-(3-o-Tolyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine15(A) N′-Hydroxy-2-methylbenzamidine

A mixture of 2-methyl-benzonitrile (0.950 mL, 8 mmol), hydroxylamine 50%in water (1.6 mL, 24 mmol) and EtOH (8 mL) was heated at 70° C. for 48h. TLC analysis (DCM/MeOH: 97/3 as eluent) indicates the completion ofthe reaction. The solvent was removed under reduced pressure to afford1.2 g of N′-hydroxy-2-methylbenzamidine (Yield: 100%) as a white powder(M.P.=147-148.5° C.). which can be used without further purification.

Rf Amidoxime (DCM/MeOH:97/3 as eluent): 0.2

15(B) 5-(But-3-ynyl)-3-o-tolyl-1,2,4-oxadiazole

In a reactor tube, a mixture of N′-hydroxy-2-methylbenzamidine (555 mg,3.7 mmol), 4-pentynoic acid (363 mg, 3.7 mmol), HOBT (0.56 g, 3.7 mmol)and EDCI.HCl (1.06 g, 5.55 mmol) in dioxane (7.4 mL) was stirred at R.Tfor 3 h. After this time the mixture was heated at 80° C. overnight in areaction block. The mixture was concentrated. The organic layer waswashed with water, NaOH 1N and water. The solvent was evaporated in aGenevac for 75 min at 40° C. using the low boiling point program. Thecrude product was purified by flash chromatography (Prepacked 10 gsilicagel column) with DCM as eluent to afford 250 mg of5-(but-3-ynyl)-3-o-tolyl-1,2,4-oxadiazole (Yield: 32%) as yellow oil.

LCMS (RT): 4.36 min; MS (ES+) gave m/z: 213.1

Rf Oxadiazole (DCM/MeOH: 99/1 as eluent): 0.75

15(C) 2-(4-(3-o-Tolyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

In a dry reaction tube containing in suspension copper iodide (11 mg,0.06 mmol) and triethylamine (3.3 mL, 24 mmol), were added2-bromopyridine (115 μL, 1.2 mmol) and the Pd(PPh₃)₂Cl₂ (42 mg, 0.06mmol) under N₂. A yellow suspension is obtained and after 5 min ofstiffing at room temperature 5-(but-3-ynyl)-3-o-tolyl-1,2,4-oxadiazole(249 mg, 1.2 mmol) in solution in 0.7 mL of triethylamine was addedunder N₂. Immediately the color of the reaction turns to black. Themixture was stirred at room temperature for 30 min and then at 80° C.for 20 h under N₂. Triethylamine was concentrated under reduced pressureand the residue was dissolved in DCM. The organic layer was washed withNH₄Cl, water, NaCl, dried (MgSO₄), and concentrated. The crude productwas purified by flash chromatography (Prepacked 10 g silicagel columnwith DCM/MeOH: 99/1 as eluent) to afford 103 mg of2-(4-(3-o-tolyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 30%)as brown semi-solid.

LCMS (RT): 4.11 min; MS (ES+) gave m/z: 290.1

¹H-NMR (CDCl₃), δ (ppm): 8.76 (s, H), 8.01 (m, H), 7.81 (m, H), 7.72 (m,H), 7.41-7.31 (m, 4H), 3.37 (m, 2H), 3.04 (m, 2H), 2.63 (s, 3H).

Example 16 2-(4-(3-Benzyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 16(A)N′-Hydroxy-2-phenylacetamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-phenylacetonitrile (0.93 mL, 8 mmol)afforded 1.2 g of N′-hydroxy-2-phenylacetamidine (Yield: 100%) as beigepowder (M.P.=58-60° C.).

16(B) 3-Benzyl-5-(but-3-ynyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 15(B), the conversion of N′-hydroxy-2-phenylacetamidine (555 mg,3.7 mmol) afforded 165 mg of 3-benzyl-5-(but-3-ynyl)-1,2,4-oxadiazole(Yield: 21%) as yellow oil.

LCMS (RT): 3.89 min; MS (ES+) gave m/z: 213.1

16(C) 2-(4-(3-Benzyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of3-benzyl-5-(but-3-ynyl)-1,2,4-oxadiazole (165 mg, 0.8 mmol) afforded 22mg of 2-(4-(3-benzyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield:10%) as brown oil.

LCMS (RT): 3.61 min; MS (ES+) gave m/z: 290.1

¹H-NMR (CDCl₃), δ (ppm): 8.76 (s, H), 7.72 (t, H), 7.35-7.24 (m, 7H),4.08 (s, 2H), 3.22 (m, 2H), 2.95 (m, 2H).

Example 172-(4-(3-(2-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 17(A)(2-(2-Fluorophenyl)-N′-hydroxyacetamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-(2-fluorophenyl)acetonitrile (1.03mL, 8 mmol) afforded 1.33 g of 2-(2-fluorophenyl)-N′-hydroxyacetamidine(Yield: 99%) as white powder (M.P.=85-87° C.).

17(B) 3-(2-Fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 15(B), the conversion of2-(2-fluorophenyl)-N′-hydroxyacetamidine (622 mg, 3.7 mmol) afforded 212mg of 3-(2-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield: 25%) asyellow oil.

LCMS (RT): 3.96 min; MS (ES+) gave m/z: 231.1

17(C) 2-(4-(3-(2-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of3-(2-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (212 mg, 0.9 mmol)afforded 15 mg of2-(4-(3-(2-fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 5%) as brown oil.

LCMS (RT): 3.63 min; MS (ES+) gave m/z: 308.1

¹H-NMR (CDCl₃), δ (ppm): 8.76 (s, H), 7.85 (s, H), 7.70 (m, H),7.33-7.22 (m, 3H), 7.12-7.04 (m, 2H), 4.13 (s, 2H), 3.26 (m, 2H), 3.01(m, 2H).

Example 182-(4-(3-(2-Methylbenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 18(A)N′-Hydroxy-2-o-tolylacetamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-o-tolylacetonitrile (1 mL, 8 mmol)afforded 1.3 g of N′-hydroxy-2-O— tolylacetamidine (Yield: 99%) as whitepowder (M.P.=116-118° C.).

18(B) 3-(2-Methylbenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 15(B), the conversion of N′-hydroxy-2-o-tolylacetamidine (607mg, 3.7 mmol) afforded 126 mg of3-(2-methylbenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield: 15%) asyellow oil.

LCMS (RT): 4.16 min; MS (ES+) gave m/z: 227.1

18(C) 2-(4-(3-(2-Methylbenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of3-(2-methylbenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (126 mg, 0.6 mmol)afforded 68 mg of2-(4-(3-(2-methylbenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 37%) as brown oil.

LCMS (RT): 3.84 min; MS (ES+) gave m/z: 304

¹H-NMR (CDCl₃), δ (ppm): 8.57 (d, H), 7.68 (t, H), 7.35 (t, H),7.30-7.22 (m, 3H), 7.12-7.12 (m, 2H), 4.07 (s, 2H), 3.21 (t, 2H), 2.97(t, 2H), 2.38 (s, 3H).

Example 192-(4-(3-(4-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 19(A)2-(4-Fluorophenyl)-N′-hydroxyacetamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-(4-fluorophenyl)acetonitrile (0.97mL, 8 mmol) afforded 1.34 g of 2-(4-fluorophenyl)-N′-hydroxyacetamidine(Yield: 100%) as white powder (M.P.=104-106° C.).

19(B) 3-(4-Fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 15(B), the conversion of2-(4-fluorophenyl)-N′-hydroxyacetamidine (622 mg, 3.7 mmol) afforded 388mg of 3-(4-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield: 46%) asyellow oil.

LCMS (RT): 4.01 min; MS (ES+) gave m/z: 231.1

19(C) 2-(4-(3-(4-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of3-(4-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (388 mg, 1.7 mmol)afforded 80 mg of2-(4-(3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 15%) as brown oil.

LCMS (RT): 3.71 min; MS (ES+) gave m/z: 308.1

¹H-NMR (CDCl₃), δ (ppm): 8.57 (s, H), 7.80 (s, H), 7.33-7.28 (m, 4H),7.02-6.96 (m, 2H), 4.05 (s, 2H), 3.26 (m, 2H), 2.96 (m, 2H).

Example 202-(4-(3-(4-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 20(A)N′-Hydroxy-2-(4-methoxyphenyl)acetamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-(4-methoxyphenyl)acetonitrile (1.09mL, 8 mmol)afforded 1.43 g of N′-hydroxy-2-(4-methoxyphenyl)acetamidine(Yield: 99%) as white powder (M.P.=104-106° C.).

20(B) 3-(4-Methoxybenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 15(B), the conversion ofN′-hydroxy-2-(4-methoxyphenyl)acetamidine (666 mg, 3.7 mmol) afforded211 mg of 3-(4-methoxybenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield:24%) as yellow oil.

LCMS (RT): 3.89 min; MS (ES+) gave m/z: 243.1

20(C) 2-(4-(3-(4-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of3-(4-methoxybenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (211 mg, 0.9 mmol)afforded 33 mg of2-(4-(3-(4-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 11%) as brown oil.

LCMS (RT): 3.56 min; MS (ES+) gave m/z: 320.1

¹H-NMR (CDCl₃), δ (ppm): 8.57 (s, H), 7.80 (s, H), 7.28-7.26 (m, 4H),6.87-6.83 (m, 2H), 4.02 (s, 2H), 3.78 (s, 3H), 3.24 (m, 2H), 2.96 (m,2H).

Example 21 2-(4-(3-Isopropyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine21(A) N′-Hydroxy-isobutyramidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of isobutyronitrile (0.75 mL, 8 mmol)afforded 0.81 g of N′-hydroxy-isobutyramidine (Yield: 99%) as colorlessoil.

21(B) 5-(But-3-ynyl)-3-isopropyl-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 15(B), the conversion of N′-hydroxy-isobutyramidine (378 mg, 3.7mmol) afforded 151 mg of 5-(but-3-ynyl)-3-isopropyl-1,2,4-oxadiazole(Yield: 25%) as yellow oil.

LCMS (RT): 3.16 min; MS (ES+) gave m/z: 165.1

21(C) 2-(4-(3-Isopropyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of5-(but-3-ynyl)-3-isopropyl-1,2,4-oxadiazole (151 mg, 0.9 mmol) afforded62 mg of 2-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 29%) as brown oil.

LCMS (RT): 2.93 min; MS (ES+) gave m/z: 242.1

¹H-NMR (CDCl₃), δ (ppm): 8.57 (s, H), 7.80 (s, H), 7.50-7.30 (m, 2H),3.27 (m, 2H), 3.12 (m, H), 2.98 (m, 2H), 1.36 (d, 6H).

Example 22 2-(4-(3-Butyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 22(A)N′-Hydroxypentanamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of pentanenitrile (0.85 mL, 8 mmol)afforded 0.91 g of N′-hydroxypentanamidine (Yield: 98%) as colorlessoil.

22(B) 5-(But-3-ynyl)-3-butyl-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 15(B), the conversion of N′-hydroxypentanamidine (430 mg, 3.7mmol) afforded 205 mg of 5-(but-3-ynyl)-3-butyl-1,2,4-oxadiazole (Yield:31%) as yellow oil.

LCMS (RT): 3.75 min; MS (ES+) gave m/z: 179.1

22(C) 2-(4-(3-Butyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of 5-(but-3-ynyl)-3-butyl-1,2,4-oxadiazole(205 mg, 1.2 mmol) afforded 28 mg of2-(4-(3-butyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 9%) asbrown oil.

LCMS (RT): 3.44 min; MS (ES+) gave m/z: 256.1

¹H-NMR (CDCl₃), δ (ppm): 8.57 (s, H), 7.65 (t, H), 7.40 (m, H), 7.25 (m,H), 3.23 (t, 2H), 2.98 (t, 2H), 2.74 (t, 2H), 1.74 (m, 2H), 1.40 (m,2H), 0.94 (t, 3H).

Example 232-(4-(3-(3-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 23(A)2-(3-Fluorophenyl)-N′-hydroxyacetamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-(3-fluorophenyl)acetonitrile (0.94mL, 8 mmol) afforded 1.34 g of 2-(3-fluorophenyl)-N′-hydroxyacetamidine(Yield: 99%) as yellow semi-solid.

23(B) 3-(3-Fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 15(B), the conversion of2-(3-fluorophenyl)-N′-hydroxyacetamidine (622 mg, 3.7 mmol) afforded 209mg of 3-(3-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield: 25%) asyellow oil.

LCMS (RT): 4.03 min; MS (ES+) gave m/z: 231.1

23(C) 2-(4-(3-(3-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of3-(3-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (209 mg, 0.9 mmol)afforded 63 mg of2-(4-(3-(3-fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 23%) as brown oil.

LCMS (RT): 3.69 min; MS (ES+) gave m/z: 308.1

¹H-NMR (CDCl₃), δ (ppm): 8.57 (s, H), 7.70 (t, H), 7.32-7.24 (m, 3H),7.12-7.09 (d, H), 7.06-7.02 (s, H), 6.98-6.92 (m, H), 4.07 (s, 2H), 3.21(t, 2H), 2.96 (t, 2H).

Example 242-(4-(3-(3-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 24(A)N′-Hydroxy-2-(3-methoxyphenyl)acetamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-(3-methoxyphenyl)acetonitrile (1.09mL, 8 mmol) afforded 1.43 g of N′-hydroxy-2-(3-methoxyphenyl)acetamidine(Yield: 99%) as yellow oil.

24(B) 3-(3-Methoxybenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 15(B), the conversion ofN′-hydroxy-2-(3-methoxyphenyl)acetamidine (667 mg, 3.7 mmol) afforded259 mg of 3-(3-methoxybenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield:29%) as yellow oil.

LCMS (RT): 3.91 min; MS (ES+) gave m/z: 243.1

24(C) 2-(4-(3-(3-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of3-(3-methoxybenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (259 mg, 1.1 mmol)afforded 60 mg of2-(4-(3-(3-methoxybenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 17%) as brown oil.

LCMS (RT): 3.64 min; MS (ES+) gave m/z: 320.1

¹H-NMR (CDCl₃), δ (ppm): 8.57 (s, H), 7.70 (t, H), 7.25-7.20 (m, 3H),6.94-6.86 (m, 2H), 6.80 (m, H), 4.05 (s, 2H), 3.78 (s, 3H), 3.21 (t,2H), 2.96 (t, 2H).

Example 252-(4-(3-(2-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 25(A)2-Fluoro-N′-hydroxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-fluorobenzonitrile (0.86 mL, 8 mmol)afforded 1.22 g of 2-fluoro-N′-hydroxybenzamidine (Yield: 99%) as yellowoil.

25(B) 5-(But-3-ynyl)-3-(2-fluorophenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 15(B), the conversion of 2-fluoro-N′-hydroxybenzamidine (570 mg,3.7 mmol) afforded 405 mg of5-(but-3-ynyl)-3-(2-fluorophenyl)-1,2,4-oxadiazole (Yield: 51%) asyellow oil. LCMS (RT): 3.99 min; MS (ES+) gave m/z: 217.1

25(C) 2-(4-(3-(2-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of5-(but-3-ynyl)-3-(2-fluorophenyl)-1,2,4-oxadiazole (405 mg, 1.9 mmol)afforded 58 mg of2-(4-(3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 10%) as brown oil.

LCMS (RT): 3.68 min; MS (ES+) gave m/z: 294.1

¹H-NMR (CDCl₃), δ (ppm): 8.57 (s, H), 8.05 (t, H), 7.70 (m, H),7.53-7.48 (m, H), 7.32-7.22 (m, 4H), 3.37 (m, 2H), 3.06 (m, 2H).

Example 262-(4-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 26(A)3-Fluoro-N′-hydroxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 3-fluorobenzonitrile (0.65 mL, 8 mmol)afforded 0.97 g of 3-fluoro-N′-hydroxybenzamidine (Yield: 99%) as yellowoil.

26(B) 5-(But-3-ynyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 15(B), the conversion of 3-fluoro-N′-hydroxybenzamidine (570 mg,3.7 mmol) afforded 336 mg of5-(but-3-ynyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole (Yield: 42%) asyellow oil. LCMS (RT): 4.31 min; MS (ES+) gave m/z: 217.1

26(C) 2-(4-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of5-(but-3-ynyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole (336 mg, 1.6 mmol)afforded 57 mg of2-(4-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 12%) as brown oil.

LCMS (RT): 3.99 min; MS (ES+) gave m/z: 294.1

¹H-NMR (CDCl₃), δ (ppm): 8.57 (s, H), 7.90 (s, H), 7.80 (d, H), 7.70 (m,H), 7.53-7.48 (m, 2H), 7.32-7.18 (m, 2H), 3.33 (m, 2H), 3.07 (m, 2H).

Example 27 5-Chloro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 27(A)Pent-4-ynimidic acid methyl ester

Sodium (291 mg, 12.6 mmol) was dissolved in dry MeOH (40 mL).Pent-4-ynenitrile (2.00 g, 25.3 mmol) was added to the reaction mixtureand the solution was stirred for 2 days at room temperature. Acetic acid(746 μL) was added followed by evaporation of the solvent to yield 1.20g (10.8 mmol, 43%) of pent-4-ynimidic acid methyl ester as a whitesolid.

27(B) 2-(But-3-ynyl)-5-chlorobenzo[d]oxazole

A mixture of pent-4-ynimidic acid methyl ester (142 mg, 1.28 mmol) and2-amino-4-chlorophenol (227 mg, 1.53 mmol) in dichloroethane (10 mL) wasstirred for 2 days under reflux. The solvent was evaporated, the residuewas partly dissolved in MeOH and filtered. The filtrate wasconcentrated, and the resulting crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 18 mg (87 μmol, 7%) of2-(but-3-ynyl)-5-chlorobenzo[d]oxazole.

27(C) 5-Chloro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (15 mg, 96 μmol) and2-(but-3-ynyl)-5-chlorobenzo[d]oxazole (18 mg, 87 μmol). Reaction time:14 hours. The crude residue was purified by flash chromatography(DCM/MeOH 99:1) to yield 6.5 mg (23 μmol, 26%) of5-chloro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a yellowsolid.

LCMS (RT): 3.84 min; MS (ES+) gave m/z: 283.0, 285.0.

¹H-NMR (CDCl₃), δ (ppm): 3.11 (t, J=7.5, 2H), 3.33 (t, J=7.5, 2H), 7.30(dd, J=2.5 and 9.0, 1H), 7.33-7.41 (m, 1H), 7.43 (d, J=9.0, 1H), 7.48(d, J=7.5, 1H), 7.67 (d, J=1.5, 1H), 7.79-7.87 (m, 1H), 8.60 (d, J=5.0,1H).

Example 28 5-Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 28(A)2-(But-3-ynyl)-5-methylbenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 27(B) from 2-amino-4-methylphenol (181 mg, 1.43 mmol). Theresulting crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 19 mg (0.1 mmol, 7%) of2-(but-3-ynyl)-5-methylbenzo[d]oxazole.

28(B) 5-Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (16 mg, 0.1 mmol) and2-(but-3-ynyl)-5-methylbenzo[d]oxazole (19 mg, 0.1 mmol). Reaction time:14 hours. The crude residue was purified by flash chromatography(DCM/MeOH 99:1) and SCX column (DCM/MeOH 95:5, DCM/MeOH/NH₄OH 90:10:0.1to 88:10:2) to yield 2.0 mg (7.6 mmol, 8%) of5-methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a yellowsolid.

LCMS (RT): 3.63 min; MS (ES+) gave m/z: 263.1.

Rf (DCM/MeOH 97:3)=0.1.

Example 29 6-Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 29(A)2-(But-3-ynyl)-6-methylbenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 27(B) from 2-amino-5-methylphenol (192 mg, 1.52 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 9:1) toyield 14 mg (77 μmol, 6%) of 2-(but-3-ynyl)-6-methylbenzo[d]oxazole.

29(B) 6-Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (14 mg, 89 mmol) and2-(but-3-ynyl)-6-methylbenzo[d]oxazole (15 mg, 81 μmol). Reaction time:14 hours. The crude residue was purified by flash chromatography(DCM/MeOH 99:1) and SCX column (DCM/MeOH 95:5, DCM/MeOH/NH₄OH 90:10:0.1to 88:10:2) to yield 7.0 mg (27 mmol, 33%) of6-methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a yellowsolid.

LCMS (RT): 3.53 min; MS (ES+) gave m/z: 263.1.

¹H-NMR (CDCl₃), δ (ppm): 2.48 (s, 3H), 3.09 (t, J=7.5, 2H), 3.30 (t,J=7.5, 2H), 7.13 (d, J=8.0, 1H), 7.30 (s, 1H), 7.31-7.37 (m, 1H), 7.46(d, J=8.0, 1H), 7.55 (d, J=8.0, 1H), 7.75-7.82 (m, 1H), 8.59 (d, J=5.0,1H).

Example 30 4-Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 30(A)2-(But-3-ynyl)-4-methylbenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 27(B) from 2-amino-3-methylphenol (183 mg, 1.48 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 9:1) toyield 12 mg (66 μmol, 5%) of 2-(but-3-ynyl)-4-methylbenzo[d]oxazole.

30(B) 4-Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (12 mg, 77 μmol) and2-(but-3-ynyl)-4-methylbenzo[d]oxazole (13 mg, 70 μmol). Reaction time:14 hours. The crude residue was purified by flash chromatography(DCM/MeOH 99:1) and SCX column (DCM/MeOH 95:5, DCM/MeOH/NH₄OH 90:5:0.1to 87:10:3) to yield 7.0 mg (27 mmol, 38%) of4-methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orangesolid.

LCMS (RT): 3.61 min; MS (ES+) gave m/z: 263.1.

¹H-NMR (CDCl₃), δ (ppm): 2.60 (s, 3H), 3.11 (t, J=8.0, 2H), 3.33 (t,J=8.0, 2H), 7.11 (d, J=7.5, 1H), 7.17-7.24 (m, 1H), 7.32 (d, J=7.5, 1H),7.37-7.45 (m, 1H), 7.50 (d, J=8.0, 1H), 7.81-7.90 (m, 1H), 8.61 (d,J=4.5, 1H).

Example 31 2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 4-bromo-2-methylthiazole (47 mg, 2.7 mmol) and2-(but-3-ynyl)benzo[d]oxazole (454 mg, 2.65 mmol, Example 8(A)). Thereaction mixture was stirred for one day under reflux. The crude residuewas purified by flash chromatography (cyclohexane/AcOEt 4:1) andtrituration with pentane to yield 14 mg (52 μmol, 2%) of2-(4-(2-methylthiazol-4-yl)but-3-ynyl)benzo[d]oxazole as a beige solid.

Example 32 2-(4-(5-Phenyl-2H-tetrazol-2-yl)but-1-ynyl)pyridine 32(A)4-(Pyridin-2-yl)but-3-yn-1-ol

In a dry reaction tube containing in suspension iodide copper (38 mg,0.2 mmol) and triethylamine (11 mL, 80 mmol), were added 2-bromopyridine(632 mg, 4 mmol) and Pd(PPh₃)₂Cl₂ (140 mg, 0.2 mmol). A yellowsuspension is obtained and after a few minutes of stiffing at roomtemperature, was added a solution of but-3-yn-1-ol (280 mg, 4 mmol) intriethylamine (2.2 mL). Immediately the color of the reaction turns toblack. The mixture was stirred at room temperature for 30 min and thenat 80° C. for 20 h. Triethylamine was concentrated under reducedpressure and the residue was dissolved in DCM. The organic layer waswashed with saturated NH₄Cl, water and brine, dried (MgSO₄) andconcentrated. The product was purified by flash chromatography(prepacked 15 g silicagel column, from DCM 100% to DCM/MeOH:98/2 aseluent) to afford 440 mg of 4-(pyridin-2-yl)but-3-yn-1-ol

(Yield: 74%) as brown oil.

Rf: (DCM/MeOH: 95/5)=0.5

LCMS (RT): 0.60 min; MS (ES+) gave m/z: 148.1

32(B) 2-(4-(5-Phenyl-2H-tetrazol-2-yl)but-1-ynyl)pyridine

A mixture of 5-phenyl-2H-tetrazole (330 mg, 2.2 mmol),4-(pyridin-2-yl)but-3-yn-1-ol (220 mg, 1.49 mmol) and triphenylphosphinepolymer supported (750 mg, 2.2 mmol, loading 3 mmol/g) were dissolvedDCM (3 mL) and stirred at 0° C. Diisoprpylazodicarboxylate (452 mg, 2.2mmol) was added dropwise, at 0° C. over a period of 30 min. The reactionmixture was then warmed to room temperature and stirred over night. Thereaction mixture was filtered through celite and the cake was washedwith DCM. The combined organic layers were washed with aqueous ammoniac,brine, dried over MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography (prepacked 25 g silicagel column, DCM100% as eluent) to afford 209 mg of2-(4-(5-phenyl-2H-tetrazol-2-yl)but-1-ynyl)pyridine (Yield: 51%) as apink powder (M.P.=71-73° C.).

Rf (DCM/MeOH:97/3)=0.4

LCMS (RT): 3.74 min; MS (ES+) gave m/z: 276.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 8.17 (m, H), 7.63 (t, H), 7.53-7.46(m, 2H), 7.36 (d, H), 7.25-7.20 (m, H), 6.36 (m, 2H), 4.93 (t, 2H), 3.25(t, 2H).

Example 33 2-(4-(Pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 33(A)Ethyl imidazo[1,2-a]pyridine-2-carboxylate

A solution of 2-amino-pyridine (2 g, 21 mmol) and ethyl bromopyruvate(4.14 g, 21 mmol) in ethanol (31 mL) was stirred under reflux for 24 h.The solvent was evaporated, and the residue was dissolved in a minimumvolume of water. The solution was neutralized (pH=8) with saturatedNaHCO₃. The aqueous layer was extracted with AcOEt and the organic layerwas washed with saturated NaCl. The solvent was removed under pressureto afford 2.51 g of ethyl imidazo[1,2-a]pyridine-2-carboxylate (Yield:62%) as an orange oil which can be used without further purification.

LCMS (RT): 0.72-1.39 min; MS (ES+) gave m/z: 191.1

Rf (DCM/MeOH: 95/5): 0.12

33(B) 2-Hydroxymethyl-imidazo[1,2-a]pyridine

In a dry round flask is added LiAlH₄ (650 mg, 17 mmol) in anhydrous THF(52 mL) under stirring. The solution was cooled to 0° C. A solution ofethyl imidazo[1,2-a]pyridine-2-carboxylate (2.5 g, 13 mmol) in dry THF(3 mL) was added dropwise. The solution became green. The reactionmixture was stirred at 0° C. for 30 min and 2 h at R.T. The reactionmixture was quenched with successively 0.52 mL of water, 0.52 mL of NaOH1M and 3×0.52 mL of water. The solution is filtered over celite. Theorganic layer is evaporated to give 2.25 g of an orange liquid. Theresidue was purified by flash chhromatography over silicagel (prepacked70 g silicagel column, DCM/MeOH:95/5 as eluent) to afford 1 g of2-hydroxymethyl-imidazo[1,2-a]pyridine (Yield: 51%) as a brown il.

LCMS (RT): 0.62; MS (ES+) gave m/z: 149.1

Rf (DCM/MeOH: 95/5): 0.13

33(C) 2-(Chloromethyl)-imidazo[1,2-a]pyridine

In a round bottomed flask containing2-hydroxymethyl-imidazo[1,2-a]pyridine (800 mg, 5.4 mmol) in DCM (8 mL),was added at R.T. thionyl chloride (1.96 mL, 27 mmol). The solutionbecame clear and 10 min later, a precipitated was formed. The reactionmixture was stirred at R.T. for 2 hours and the solvent was removedunder reduced pressure to afford 1.10 g of a brownish solid as thechlorhydrate form of 2-(chloromethyl)-imidazo[1,2-a]pyridine (Yield:100%).

To saturated NaHCO₃ (40 mL) was added the chlorhydrate form of2-(chloromethyl)-imidazo[1,2-a]pyridine and the aqueous layer wasextracted with AcOEt. The organic layers were combined and washed withbrine, dried over MgSO₄ and the solvent was removed under reducedpressure to afford 877 mg of 2-(chloromethyl)-imidazo[1,2-a]pyridine(Yield. 80%). as a brownish solid (M.P.: 84-85° C.)

LCMS (RT): 0.64; MS (ES+) gave m/z: 167.1

33(D) 2-(4-(Trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(C), the conversion of2-(chloromethyl)-imidazo[1,2-a]pyridine (200 mg, 1.2 mmol) afforded 155mg of 2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:53%) as yellow oil.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, DCM/MeOH from 99/1 to 98/2 as eluent).

LCMS (RT): 0.54-2.71 min; MS (ES+) gave m/z: 243.1

Rf (DCM/MeOH: 95/5): 0.42

33(E) 2-(But-3-ynyl)-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(D), the conversion of2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (140 mg, 0.67mmol) afforded 70 mg of 2-(but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:71%) as yellow oil.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, DCM/MeOH from 99/1 to 98/2 as eluent).

LCMS (RT): 0.54 min; MS (ES+) gave m/z: 171.1

Rf (DCM/MeOH: 95/5): 0.27

33(F) 2-(4-(Pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of 2-(but-3-ynyl)-imidazo[1,2-a]pyridine(70 mg, 0.41 mmol) afforded 34 mg of2-(4-(Pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 33%) asyellow oil.

Purification over silicagel chromatography (prepacked 10 g silicagelcolumn, DCM/MeOH from 100/0 to 99/1 as eluent).

LCMS (RT): 0.60-1.57 min; MS (ES+) gave m/z: 248.1

Rf (DCM/MeOH: 95/5): 0.32

¹H-NMR (CDCl₃), δ (ppm): 8.54 (d, H), 8.06 (d, H), 7.64-7.57 (m, 2H),7.50 (s, H), 7.40 (d, H), 7.20-7.12 (m, 2H), 6.75 (t, H), 3.13 (t, 2H),2.93 (t, 2H).

Example 34 N-(4-Fluorophenyl)-5-(pyridine-2-yl)pent-4-ynamide 34(A)N-(4-Fluorophenyl)pent-4-ynamide

According to the protocol described in Example 12(A), the conversion ofN4-fluorobenzenamine (566 mg, 5.10 mmol) afforded 922 mg ofN-(4-fluorophenyl)pent-4-ynamide (Yield: 95%) as brownish solid whichcan be used without further purification.

LCMS (RT): 0.64 min; MS (ES+) gave m/z: 192.1

Rf (DCM/MeOH:8/2)=0.2

34(B) tert-Butyl 4-fluorophenylpent-4-ynoylcarbamate

According to the general protocol described in J. Med. Chem., 2000, 43,20, 3718-3735, to solution of N-(4-fluorophenyl)pent-4-ynamide (200 mg,1 mmol) in DCM (3 mL) were successively added triethylamine (146 mL,1.05 mmol), (BOC)₂O (270 mg, 1.3 mmol) and DMAP (13 mg, 0.1 mmol). Afterstiffing for 18 h at room temperature, the solvent was removed underreduced pressure and the crude product was purified by flashchromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt:90/10as eluent) to afford 274 mg of tert-butyl4-fluorophenylpent-4-ynoylcarbamate (Yield: 90%) as colorless oil.

LCMS (RT): 4.11 min; MS (ES+) gave m/z: 192.1 (MH+-Boc)

Rf (Cyclohexane/AcOEt:90/10): 0.35

34(C) tert-Butyl 5-(pyridin-2-yl)pent-4-ynoyl-4-fluorophenylcarbamate

According to the protocol described in Example 38(E), the conversion oftert-butyl 4-fluorophenylpent-4-ynoylcarbamate (274 mg, 0.94 mmol)afforded 299 mg of tert-butyl5-(pyridin-2-yl)pent-4-ynoyl-4-fluorophenylcarbamate (Yield: 86%) asyellow oil.

Purification by Flash chromatography (prepacked 25 g silicagel column,DCM/MeOH:99/1 as eluent)

LCMS (RT): 3.94 min; MS (ES+) gave m/z: 369

Rf (DCM/MeOH: 98/2): 0.19

34(D) N-(4-Fluorophenyl)-5-(pyridine-2-yl)pent-4-ynamide

tert-Butyl-5-(pyridin-2-yl)pent-4-ynoyl-4-fluorophenylcarbamate (299 mg,0.81 mmol) was dissolved in DCM (4 mL) with 0.01% w/w of water. 4 mL oftrifluoroacetic acid was added at room temperature to the solution. Theresulting mixture was stirred at R.T. for 2 h. The solvent was removedunder reduced pressure. The brown oil was dissolved in saturated NaHCO₃until pH=8. The aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over MgSO₄ and thesolvent was removed under reduced pressure. The brownish solid wastritureted in a mixture Et₂O/Pentane:50/50. The solid was collected byfiltration and washed with a mixture Et₂O/Pentane:50/50. The solid wasdried by lyophilisation to afford 181 mg ofN-(4-fluorophenyl)-5-(pyridine-2-yl)pent-4-ynamide (Yield: 83%) as acolorless solid (M.P.=189.9-190.2° C.).

LCMS (RT): 2.83 min; MS (ES+) gave m/z: 269.1

Rf (DCM/MeOH: 95/5): 0.23

¹NMR (CDCl₃), δ (ppm): 8.56 (s, H), 7.68-7.61 (m, 2H), 7.54-7.49 (m,2H), 7.38 (d, H), 7.23 (m, H), 7.11 (m, 2H), 2.88 (t, 2H), 2.70 (t, 2H).

Example 35 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]thiazole 35(A)2-(But-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-aminobenzenethiol (387 mg, 3.03 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 9:1) toyield 453 mg (2.42 mmol, 80%) of 2-(but-3-ynyl)benzo[d]thiazole as anorange oil.

35(B) 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (127 mg, 0.80 mmol) and2-(but-3-ynyl)benzo[d]thiazole (150 mg, 0.80 mmol). Reaction time: 1day. The crude residue was purified by flash chromatography (DCM/MeOH99:1) to yield 96 mg (0.36 mmol, 45%) of2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as an orange solid(M.P.=98.5-99.4° C.).

LCMS (RT): 3.24 min; MS (ES+) gave m/z: 265.0.

Rf (DCM/MeOH 99:1)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.05 (t, J=7.5, 2H), 3.46 (t, J=7.5, 2H),7.18-7.22 (m, 1H), 7.35-7.39 (2H), 7.45-7.49 (m, 1H), 7.60-7.64 (m, 1H),7.84-7.87 (m, 1H), 7.99 (d, J=8.0, 1H), 8.54-8.57 (m, 1H).

Example 36 6-Chloro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 36(A)2-(But-3-ynyl)-6-chlorobenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-5-chlorophenol (290 mg, 2.02 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 9:1) toyield 262 mg (1.28 mmol, 65%) of 2-(but-3-ynyl)-6-chlorobenzo[d]oxazoleas an orange solid.

36(B) 6-Chloro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (115 mg, 0.73 mmol) and2-(but-3-ynyl)-6-chlorobenzo[d]oxazole (150 mg, 0.73 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1) to yield107 mg (0.38 mmol, 52%) of6-chloro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a yellow solid(M.P.=101.5-102.2° C.).

LCMS (RT): 3.49 min; MS (ES+) gave m/z: 283.0, 285.0.

Rf (DCM/MeOH 99:1)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.05 (t, J=7.5, 2H), 3.28 (t, J=7.5, 2H),7.18-7.22 (m, 1H), 7.29 (dd, J=2.0 and 8.5, 1H), 7.33-7.36 (m, 1H), 7.51(d, J=2.0, 1H), 7.59 (d, J=9.0, 1H), 7.59-7.63 (m, 1H), 8.53-8.55 (m,1H).

Example 37 5-Fluoro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 37(A)2-(But-3-ynyl)-5-fluorobenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-4-fluorophenol (259 mg, 2.04 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 9:1) toyield 116 mg (0.61 mmol, 30%) of 2-(but-3-ynyl)-5-fluorobenzo[d]oxazoleas a yellow solid.

37(B) 5-Fluoro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (96.9 mg, 0.61 mmol) and2-(but-3-ynyl)-5-fluorobenzo[d]oxazole (116 mg, 0.61 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1) to yield 84mg (0.31 mmol, 51%) of5-fluoro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a slightlyyellow solid (M.P.=100.1-101.0° C.).

LCMS (RT): 3.11 min; MS (ES+) gave m/z: 267.1.

Rf (DCM/MeOH 99:1)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.06 (t, J=6.5, 2H), 3.29 (t, J=6.5, 2H),7.02-7.07 (m, 1H), 7.18-7.21 (m, 1H), 7.34-7.39 (2H), 7.43 (dd, J=4.5and 9.0, 1H), 7.59-7.63 (m, 1H), 8.52-8.55 (m, 1H).

Example 38 2-(6-(4-Fluorophenyl)hexa-1,5-diynyl)pyridine 38(A)3-(4-Fluorophenyl)prop-2-yn-1-ol

In a dry flask containing in suspension copper iodide (84 mg, 0.44 mmol)and triethylamine (24.70 mL), was added Pd(PPh₃)₂Cl₂ (310 mg, 0.44 mmol)under N₂. A yellow suspension is obtained. The reaction mixture wascooled to 0° C. in an ice-bath before the addition of1-fluoro-4-iodobenzene (1.95 g, 8.80 mmol). After five minutes at 0° C.,a solution of prop-2-yn-1-ol (493 mg, 8.80 mmol) in triethylamine (4 mL)was slowly added under N₂ over a period of 15 min. Immediately the colorof the reaction turns to black. The mixture was stirred 0° C. for 30 minand then warmed to room temperature for 20 h under N₂. Triethylamine wasconcentrated under reduce pressure and the residue was dissolved in DCM.The organic layer was washed with saturated NH₄Cl, water, brine, dried(MgSO₄) and concentrated. The crude product was purified by flashchromatography (prepacked 25 g silicagel column, DCM 100% as eluent) toafford 1.10 g of 3-(4-fluorophenyl)prop-2-yn-1-ol (Yield: 83%) as ayellow oil.

Rf (DCM/MeOH:95/5)=0.5

LCMS (RT): 2.88 min, MS (ES+): no ionisation

38(B) 1-(3-Bromoprop-1-ynyl)-4-fluorobenzene

A solution of 3-(4-fluorophenyl)prop-2-yn-1-ol (1 g, 6.80 mmol) in DCM(13.6 mL) under N₂ was cooled in a ice bath at 0° C. 2.70 g (8.2 mmol,loading 3 mmol/g) of triphenylphosphine polymer supported was then addedfollowed by 2.70 g (8.2 mmol) of carbon tetrabromide. The reactionmixture was stirred 15 min at 0° C. and warmed to room temperature for90 min. After filtration through celite, the solvent was evaporatedunder reduce pressure. The crude product was purified by flashchromatography (prepacked 25 g silicagel column, DCM 100% as eluent) toafford 1.44 g of 1-(3-bromoprop-1-ynyl)-4-fluorobenzene as a yellow oil(Yield: 99%).

Rf (DCM/MeOH: 95/5)=0.6

LCMS (RT): 4.14 min, MS (ES+): no ionisation

38(C) (6-(4-Fluorophenyl)hexa-1,5-diynyl)trimethylsilane

To a solution of trimethyl(prop-1-ynyl)silane (2.19 g, 19.50 mmol) in 22mL of THF at −78° C., was added dropwise n-BuLi 2.5M in hexane (7.8 mL,20 mmol). After stiffing 2 hours at −78° C.,1-(3-bromoprop-1-ynyl)-4-fluorobenzene (1.40 g, 6.5 mmol) in 6 mL of THFwas slowly added and the resulting mixture was stirred for 1 h at −78°C. and warmed to room temperature for an additional 1 h. The reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic layer was dried over MgSO₄, filtered and concentrated to afford1.57 g of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane (99%) as ayellow oil.

LCMS (RT): 4.89 min, MS (ES+): no ionisation

38(D) 1-Fluoro-4-(hexa-1,5-diynyl)benzene

To a solution of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane(1.90 g, 7.7 mmol) in THF (24 mL) cooled in a ice bath at 0° C., wasadded dropwise 7.7 mL of tetrabutylammonium fluoride 1M in THF solution(7.70 mmol). The reaction mixture was stirred 15 min at 0° C., andwarmed to room temperature for 2 h30. The reaction was quenched withwater and the aqueous layer was extracted with diethyl ether. Theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated. The product was purified by flash chromatography(prepacked 25 g silicagel column, DCM 100% as eluent) to afford 500 mgof 1-fluoro-4-(hexa-1,5-diynyl)benzene (Yield: 45%) as a yellow oil.

LCMS (RT): 4.11 min, MS (ES+): no ionisation

38(E) 2-(6-(4-Fluorophenyl)hexa-1,5-diynyl)pyridine

In a dry reaction tube containing in suspension copper iodide (11 mg,0.06 mmol) and triethylamine (3.4 mL), were added 2-iodopyridine (246mg, 1.2 mmol) and Pd(PPh₃)₂Cl₂ (42 mg, 0.06 mmol) under N₂. A yellowsuspension was obtained after 5 min of stirring at room temperature. Asolution of 1-fluoro-4-(hexa-1,5-diynyl)benzene (210 mg, 1.2 mmol) intriethylamine (0.5 mL) was then added under N₂. Immediately the color ofthe reaction turns to black. The mixture was stirred at room temperaturefor 48 h. The reaction mixture was concentrated. The crude product wasdissolved in DCM and the organic phase was washed with saturated NH₄Cl,water and brine. The organic layer was dried over MgSO₄, filtered, andconcentrated. Purification by Flash chromatography (prepacked 25 gsilicagel column, Cyclohexane/ethyl acetate from 90/10 to 80/20 aseluent) to afford 87 mg of 2-(6-(4-fluorophenyl)hexa-1,5-diynyl)pyridine(Yield: 29%) as a brown powder (M.P.=68-69° C.).

Rf (Cyclohexane/AcOEt:80/20)=0.3

LCMS (RT): 3.91 min; MS (ES+) gave m/z: 250.1

¹NMR (CDCl₃), δ (ppm): 8.58 (d, H), 7.63 (t, H), 7.42-7.37 (m, 3H), 7.22(m, H), 7.01-6.95 (m, 2H), 2.76 (m, 4H).

Example 392-(4-(Pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one39(A) 2-(But-3-ynyl)-[1,2,4]-triazolo[4,3-a]pyridin-3(2H)-one

The title compound was prepared in accordance with the general method ofExample 109(D), from [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (405 mg,3.00 mmol) and but-3-yn-1-ol (200 mg, 2.85 mmol). The crude residue waspurified by flash chromatography (DCM/MeOH 99:1) to yield 140 mg (0.75mmol, 26%) of 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

39(B)2-(4-(Pyridin-2-yl)but-3-ynyl)-[1,2,4]-triazolo[4,3-a]pyridin-3(2H)-one

The title compound was prepared in accordance with the general method ofExample 1, from 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(70 mg, 0.37 mmol) and 2-bromopyridine (65 mg, 0.41 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 98:2) to yield 23mg (87 mmol, 23%) of2-(4-(pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-oneas a yellow solid (M.P.=95.5-96° C.).

LCMS (RT): 2.43 min; MS (ES+) gave m/z: 265.0.

Rf (DCM/MeOH 98:2)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 3.00 (t, J=7.2, 2H), 4.29 (t, J=7.2, 2H),6.46-6.51 (m, 1H), 7.08-7.11 (2H), 7.19 (ddd, J=1.1, 4.8 and 7.8, 1H),7.38 (d, J=8.1, 1H), 7.57-7.65 (m, 1H), 7.73-7.78 (m, 1H), 8.50-8.55 (m,1H).

Example 402-(4-(3-(2-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 40(A)N′-Hydroxy-2-methoxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-methoxybenzonitrile (0.86 mL, 7 mmol)afforded 1.1 g of N′-hydroxy-2-methoxybenzamidine (Yield: 95%) as whitepowder (M.P.=66-68° C.).

40(B) 5-(But-3-ynyl)-3-(2-methoxyphenyl)-1,2,4-oxadiazole

In a reactor tube, a mixture of N′-hydroxy-2-methoxybenzamidine (598 mg,3.6 mmol), 4-pentynoic acid (350 mg, 3.6 mmol), HOBT (0.55 g, 3.6 mmol)and EDCI.HCl (1.03 g, 5.4 mmol) in dioxane (7.4 mL) was stirred at R.Tfor 3 h. After this time the mixture was heated at 80° C. overnight in areaction block. The mixture was concentrated and the crude product waspurified by flash chromatography (Prepacked column 25 g with DCM aseluent) to afford 299 mg of5-(but-3-ynyl)-3-(2-methoxyphenyl)-1,2,4-oxadiazole (36%) as yellow oil.

LCMS (RT): 3.39 min; MS (ES+) gave m/z: 229.0

Rf Oxadiazole (DCM/MeOH:99/1): 0.75.

40(C) 2-(4-(3-(2-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

In a dry reaction tube containing in suspension copper iodide (12 mg,0.07 mmol) and triethylamine (4.1 mL, 29 mmol), were added2-iodopyridine (139 μL, 1.3 mmol) and Pd(PPh₃)₂Cl₂ (46 mg, 0.07 mmol)under N₂. A yellow suspension is obtained and after a few minutes ofstiffing at room temperature, was added a solution5-(but-3-ynyl)-3-(2-methoxyphenyl)-1,2,4-oxadiazole (299 mg, 1.3 mmol)in triethylamine (0.7 mL) under N₂. Immediately the color of thereaction turns to black. The mixture was stirred at room temperature for20 h under N₂. Triethylamine was removed under reduce pressure and thecrude product was purified by flash chromatography (Prepacked column 10g, cyclohexane/AcOEt: from 60/40 to 50/50 as eluent) to afford 50 mg of2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (13%)as brown oil.

LCMS (RT): 3.04 min; MS (ES+) gave m/z: 306.1

¹H-NMR (CDCl₃), δ (ppm): 8.56 (d, H), 8.01 (dd, H), 7.62 (t, H), 7.48(t, H), 7.38 (d, H), 7.23-7.18 (m, H), 7.11-7.04 (m, 2H), 3.98 (s, 3H),3.32 (t, 2H), 3.06 (t, 2H).

Example 412-(4-(3-(3-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 41(A)N′-Hydroxy-3-methoxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 3-methoxybenzonitrile (0.87 mL, 7 mmol)afforded 1.1 g of N′-hydroxy-3-methoxybenzamidine (Yield: 95%) as beigepowder (M.P.=59-61° C.).

41(B) 5-(But-3-ynyl)-3-(3-methoxyphenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of N′-hydroxy-3-methoxybenzamidine (598mg, 3.6 mmol) afforded 276 mg of5-(but-3-ynyl)-3-(3-methoxyphenyl)-1,2,4-oxadiazole (Yield: 34%) asyellow oil. LCMS (RT): 3.79 min; MS (ES+) gave m/z: 229.0

41(C) 2-(4-(3-(3-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(3-methoxyphenyl)-1,2,4-oxadiazole (276 mg, 1.2 mmol)afforded 128 mg of2-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

(Yield: 35%) as brown oil.

LCMS (RT): 3.59 min; MS (ES+) gave m/z: 306.1

¹H-NMR (CDCl₃), δ (ppm): 8.56 (d, H), 7.68 (d, H), 7.65-7.60 (m, 2H),7.41-7.36 (m, 2H), 7.22 (m, H), 7.06 (d, H), 3.88 (s, 3H), 3.32 (t, 2H),3.06 (t, 2H).

Example 422-(4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 42(A)N′-Hydroxy-4-methoxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 4-methoxybenzonitrile (0.93 g, 7 mmol)afforded 1.1 g of N′-hydroxy-4-methoxybenzamidine (Yield: 95%) as beigepowder (M.P.=113-115° C.).

42(B) 5-(But-3-ynyl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of N′-hydroxy-4-methoxybenzamidine (598mg, 3.6 mmol) afforded 343 mg of5-(but-3-ynyl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole (Yield: 42%) asyellow oil. LCMS (RT): 3.81 min; MS (ES+) gave m/z: 229.0

42(C) 2-(4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole (343 mg, 1.5 mmol)afforded 98 mg of2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 21%) as brown oil.

LCMS (RT): 3.51 min; MS (ES+) gave m/z: 306.1

¹H-NMR (CDCl₃), δ (ppm): 8.56 (d, H), 8.01-8.05 (m, 2H), 7.62 (t, H),7.38 (d, H), 7.22 (m, H), 7.02-6.97 (m, 2H), 3.88 (s, 3H), 3.28 (t, 2H),3.04 (t, 2H).

Example 43 2-(4-(3-m-Tolyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine43(A) N′-Hydroxy-3-methylbenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 3-methylbenzonitrile (0.83 mL, 7 mmol)afforded 1.03 g of N′-hydroxy-3-methylbenzamidine (Yield: 98%) as beigepowder (M.P.=86-88° C.).

43(B) 5-(But-3-ynyl)-3-m-tolyl-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of N′-hydroxy-3-methylbenzamidine (541 mg,3.6 mmol) afforded 226 mg of 5-(but-3-ynyl)-3-m-tolyl-1,2,4-oxadiazole(Yield: 30%) as yellow oil.

LCMS (RT): 3.98 min; MS (ES+) gave m/z: 213.1

43(C) 2-(4-(3-m-Tolyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-m-tolyl-1,2,4-oxadiazole (226 mg, 1.1 mmol) afforded144 mg of 2-(4-(3-m-tolyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 45%) as brown oil.

LCMS (RT): 3.76 min; MS (ES+) gave m/z: 290.1

¹NMR (CDCl₃), δ (ppm): 8.56 (d, H), 7.93-7.87 (m, 2H), 7.62 (t, H),7.41-7.36 (m, 2H), 7.32 (m, H), 7.22 (m, H), 3.31 (t, 2H), 3.06 (t, 2H),2.43 (s, 3H).

Example 44 2-(4-(3-p-Tolyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine44(A) N′-Hydroxy-4-methylbenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 4-methylbenzonitrile (0.82 g, 7 mmol)afforded 1.03 g of N′-hydroxy-4-methylbenzamidine (Yield: 98%) as whitepowder (M.P.=143-144° C.).

44(B) 5-(But-3-ynyl)-3-p-tolyl-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of N′-hydroxy-4-methylbenzamidine (541 mg,3.6 mmol) afforded 482 mg of 5-(but-3-ynyl)-3-p-tolyl-1,2,4-oxadiazole(Yield: 63%) as yellow oil.

LCMS (RT): 3.99 min; MS (ES+) gave m/z: 213.1

44(C) 2-(4-(3-p-Tolyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-p-tolyl-1,2,4-oxadiazole (482 mg, 2.3 mmol) afforded175 mg of 2-(4-(3-p-tolyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 26%) as brown oil.

LCMS (RT): 3.76 min; MS (ES+) gave m/z: 290.1

¹NMR (CDCl₃), δ (ppm): 8.56 (d, H), 7.93-7.87 (m, 2H), 7.62 (t, H), 7.38(d, H), 7.32-7.28 (m, 2H), 7.22 (m, H), 3.31 (t, 2H), 3.06 (t, 2H), 2.42(s, 3H).

Example 452-(4-(3-(2-Chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 45(A)2-Chloro-N′-hydroxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-chlorobenzonitrile (0.96 g, 7 mmol)afforded 1.01 g of 2-chloro-N′-hydroxybenzamidine (Yield: 85%) as beigepowder (M.P.=79-81° C.).

45(B) 5-(But-3-ynyl)-3-(2-chlorophenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 2-chloro-N′-hydroxybenzamidine (614 mg,3.6 mmol) afforded 210 mg of5-(but-3-ynyl)-3-(2-chlorophenyl)-1,2,4-oxadiazole (Yield: 25%) asyellow oil.

LCMS (RT): 3.83 min; MS (ES+) gave m/z: 233.0

45(C) 2-(4-(3-(2-Chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(2-chlorophenyl)-1,2,4-oxadiazole (210 mg, 0.9 mmol)afforded 124 mg of2-(4-(3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 45%) as brown oil.

LCMS (RT): 3.59 min; MS (ES+) gave m/z: 310.1

¹NMR (CDCl₃), δ (ppm): 8.56 (d, H), 7.93 (d, H), 7.62 (t, H), 7.48-7.37(m, 3H), 7.22 (m, H), 7.22 (m, H), 3.35 (t, 2H), 3.08 (t, 2H).

Example 462-(4-(3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 46(A)3-Chloro-N′-hydroxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 3-chlorobenzonitrile (0.96 g, 7 mmol)afforded 1.18 g of 3-chloro-N′-hydroxybenzamidine (Yield: 99%) as beigepowder (M.P.=103-105° C.).

46(B) 5-(But-3-ynyl)-3-(3-chlorophenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 3-chloro-N′-hydroxybenzamidine (614 mg,3.6 mmol) afforded 344 mg of5-(but-3-ynyl)-3-(3-chlorophenyl)-1,2,4-oxadiazole (Yield: 41%) asyellow oil.

LCMS (RT): 4.14 min; MS (ES+) gave m/z: 233.0

46(C) 2-(4-(3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(3-chlorophenyl)-1,2,4-oxadiazole (344 mg, 1.5 mmol)afforded 281 mg of2-(4-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 61%) as brown oil.

LCMS (RT): 3.94 min; MS (ES+) gave m/z: 310.1

¹NMR (CDCl₃), δ (ppm): 8.56 (d, H), 8.10 (t, H), 7.98 (d, H), 7.63 (t,H), 7.48 (d, H), 7.44-7.36 (m, 2H), 7.22 (m, H), 3.32 (t, 2H), 3.06 (t,2H).

Example 472-(4-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 47(A)4-Chloro-N′-hydroxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 4-chlorobenzonitrile (0.96 g, 7 mmol)afforded 1.17 g of 4-chloro-N′-hydroxybenzamidine (Yield: 98%) as beigepowder (M.P.=133-134° C.).

47(B) 5-(But-3-ynyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 4-chloro-N′-hydroxybenzamidine (614 mg,3.6 mmol) afforded 329 mg of5-(but-3-ynyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole (Yield: 39%) asyellow oil.

LCMS (RT): 4.13 min; MS (ES+) gave m/z: 233.0

47(C) 2-(4-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole (329 mg, 1.4 mmol)afforded 227 mg of2-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 52%) as white solid (M.P.=75-77° C.).

LCMS (RT): 3.93 min; MS (ES+) gave m/z: 310

¹NMR (CDCl₃), δ (ppm): 8.56 (d, H), 8.06-8.02 (m, 2H), 7.63 (t, H),7.49-7.45 (m, 2H), 7.38 (d, H), 7.22 (m, H), 3.31 (t, 2H), 3.06 (t, 2H).

Example 482-(4-(3-(2,6-Dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine48(A) N′-Hydroxy-2,6-dimethylbenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2,6-dimethylbenzonitrile (0.92 g, 7mmol) afforded 0.95 g of N′-hydroxy-2,6-dimethylbenzamidine (Yield: 83%)as beige powder (M.P.=77-79° C.).

48(B) 5-(But-3-ynyl)-3-(2,6-dimethylphenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of N′-hydroxy-2,6-dimethylbenzamidine (591mg, 3.6 mmol) afforded 485 mg of5-(but-3-ynyl)-3-(2,6-dimethylphenyl)-1,2,4-oxadiazole (Yield: 60%) asyellow oil.

LCMS (RT): 3.88 min; MS (ES+) gave m/z: 227.1

48(C)2-(4-(3-(2,6-Dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(2,6-dimethylphenyl)-1,2,4-oxadiazole (485 mg, 2.1mmol) afforded 71 mg of2-(4-(3-(2,6-dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

(Yield: 11%) as a brown oil.

LCMS (RT): 3.61 min; MS (ES+) gave m/z: 304.1

¹NMR (CDCl₃), δ (ppm): 8.56 (d, H), 7.63 (t, H), 7.48 (d, H), 7.29-7.22(m, 2H), 7.12-7.08 (d, 2H), 3.35 (t, 2H), 3.07 (t, 2H).

Example 492-(4-(3-(2-Trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine49(A) 2-(Trifluoromethyl)-N′-hydroxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-(trifluoromethyl)benzonitrile (1.2 g,7 mmol) afforded 1.4 g of 2-(trifluoromethyl)-N′-hydroxybenzamidine(Yield: 99%) as white powder (M.P.=74-76° C.).

49(B) 5-(But-3-ynyl)-3-(2-(trifluoromethyl)phenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of2-(trifluoromethyl)-N′-hydroxybenzamidine (735 mg, 3.6 mmol) afforded126 mg of 5-(but-3-ynyl)-3-(2-(trifluoromethyl)phenyl)-1,2,4-oxadiazole(Yield: 13%) as yellow oil,

LCMS (RT): 3.89 min; MS (ES+) gave m/z: 267.0

49(C)2-(4-(3-(2-Trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(2-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (126 mg,0.5 mmol) afforded 66 mg of2-(4-(3-(2-trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 39%) as a brown oil.

LCMS (RT): 3.61 min; MS (ES+) gave m/z: 344.1

¹NMR (CDCl₃), δ (ppm): 8.56 (d, H), 7.87-7.78 (m, 2H), 7.68-7.62 (m,3H), 7.38 (d, H), 7.22 (m, H), 3.35 (t, 2H), 3.07 (t, 2H).

Example 502-(4-(3-(Naphthalen-1-yl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 50(A)N′-Hydroxy-1-naphthamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 1-naphthonitrile (1.07 g, 7 mmol)afforded 1.28 g of N′-hydroxy-1-naphthamidine (Yield: 98%) as whitepowder (M.P.=128-130° C.).

50(B) 5-(But-3-ynyl)-3-(naphthalen-1-yl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of N′-hydroxy-1-naphthamidine (670 mg, 3.6mmol) afforded 264 mg of5-(but-3-ynyl)-3-(naphthalen-1-yl)-1,2,4-oxadiazole (Yield: 30%) asyellow oil.

LCMS (RT): 4.24 min; MS (ES+) gave m/z: 249.1

50(C) 2-(4-(3-(Naphthalen-1-yl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(naphthalen-1-yl)-1,2,4-oxadiazole (264 mg, 1.1 mmol)afforded 105 mg of2-(4-(3-(naphthalen-1-yl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 29%) as a brown oil.

LCMS (RT): 4.03 min; MS (ES+) gave m/z: 326.1

¹NMR (CDCl₃), δ (ppm): 8.91 (d, H), 8.56 (d, H), 8.26 (d, H), 8.02 (d,H), 7.93 (d, H), 7.66-7.56 (m, 4H), 7.40 (d, H), 7.22 (m, H), 3.39 (t,2H), 3.13 (t, 2H).

Example 512-(4-(3-(Naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 51(A)N′-Hydroxy-2-naphthamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-naphthonitrile (1.07 g, 7 mmol)afforded 1.27 g of N′-hydroxy-2-naphthamidine (Yield: 98%) as whitepowder (M.P.=147-149° C.).

51(B) 5-(But-3-ynyl)-3-(naphthalen-2-yl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of N′-hydroxy-2-naphthamidine (670 mg, 3.6mmol) afforded 436 mg of5-(but-3-ynyl)-3-(naphthalen-2-yl)-1,2,4-oxadiazole (Yield: 49%) asyellow oil.

LCMS (RT): 4.29 min; MS (ES+) gave m/z: 249.0

51(C) 2-(4-(3-(Naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(naphthalen-2-yl)-1,2,4-oxadiazole (436 mg, 1.8 mmol)afforded 152 mg of2-(4-(3-(naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 26%) as white solid (M.P.=76-78° C.).

LCMS (RT): 4.11 min; MS (ES+) gave m/z: 326.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 8.54 (d, H), 8.15 (d, H), 7.99-7.93(m, 2H), 7.90 (d, H), 7.65-7.60 (m, H), 7.58-7.53 (m, 2H), 7.40 (d, H),7.22 (m, H), 3.36 (t, 2H), 3.11 (t, 2H).

Example 522-(4-(3-(2,3-Dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine52(A) N′-Hydroxy-2,3-dimethylbenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of (2,3-dimethylbenzonitrile (0.92 g, 7mmol) afforded 1.12 g of N′-hydroxy-2,3-dimethylbenzamidine (Yield: 97%)as white powder (M.P.=110-111° C.).

52(B) 5-(But-3-ynyl)-3-(2,3-dimethylphenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of N′-hydroxy-2,3-dimethylbenzamidine (558mg, 3.4 mmol) afforded 345 mg of5-(but-3-ynyl)-3-(2,3-dimethylphenyl)-1,2,4-oxadiazole (Yield: 45%) asyellow oil.

LCMS (RT): 4.01 min; MS (ES+) gave m/z: 227.1

52(C)2-(4-(3-(2,3-Dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(2,3-dimethylphenyl)-1,2,4-oxadiazole (345 mg, 1.5mmol) afforded 175 mg of2-(4-(3-(2,3-dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 38%) as brown oil.

LCMS (RT): 3.81 min; MS (ES+) gave m/z: 304.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 7.70-7.61 (m, 2H), 7.40 (d, H),7.32-7.18 (m, 3H), 3.33 (t, 2H), 3.07 (t, 2H), 2.47 (s, 3H), 2.37 (s,3H).

Example 532-(4-(3-(2,5-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine53(A) 2,5-Dichloro-N′-hydroxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2,5-dichlorobenzonitrile (1.21 mmol)afforded 1.35 g of 2,5-dichloro-N′-hydroxybenzamidine (Yield: 94%) asyellow oil.

53(B) 5-(But-3-ynyl)-3-(2,5-dichlorophenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 2,5-dichloro-N′-hydroxybenzamidine (697mg, 3.4 mmol) afforded 425 mg of5-(but-3-ynyl)-3-(2,5-dichlorophenyl)-1,2,4-oxadiazole (Yield: 47%) asyellow oil.

LCMS (RT): 4.21 min; MS (ES+) gave m/z: 267.0

53(C)2-(4-(3-(2,5-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(2,5-dichlorophenyl)-1,2,4-oxadiazole (425 mg, 1.6mmol) afforded 34 2 mg of2-(4-(3-(2,5-dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 65%) as brown semi-solid.

LCMS (RT): 4.06 min; MS (ES+) gave m/z: 346.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 7.97 (d, H), 7.63 (t, H), 7.48 (d,H), 7.43-7.37 (m, 2H), 7.22 (t, H), 3.35 (t, 2H), 3.07 (t, 2H).

Example 542-(4-(3-(2,5-Dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine54(A) N′-Hydroxy-2,5-dimethylbenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2,5-dimethylbenzonitrile (0.92 g, 7mmol) afforded 1.14 g of N′-hydroxy-2,5-dimethylbenzamidine (Yield: 99%)as yellow oil.

54(B) 5-(But-3-ynyl)-3-(2,5-dimethylphenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of N′-hydroxy-2,5-dimethylbenzamidine (558mg, 3.4 mmol) afforded 329 mg of5-(but-3-ynyl)-3-(2,5-dimethylphenyl)-1,2,4-oxadiazole (Yield: 43%) asyellow oil.

LCMS (RT): 4.18 min; MS (ES+) gave m/z: 227.1

54(C)2-(4-(3-(2,5-Dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of (329 mg, 1.5 mmol) of5-(but-3-ynyl)-3-(2,5-dimethylphenyl)-1,2,4-oxadiazole afforded 58 mg of2-(4-(3-(2,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 13%) as brown oil.

LCMS (RT): 3.98 min; MS (ES+) gave m/z: 304.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 7.80 (s, H), 7.65 (t, H), 7.40 (d,H), 7.25-7.18 (m, 3H), 3.32 (t, 2H), 3.08 (t, 2H), 2.58 (s, 3H), 2.38(s, 3H).

Example 552-(4-(3-(2,6-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine55(A) 2,6-Dichloro-N′-hydroxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2,6-dichlorobenzonitrile (1.20 g, 7mmol) afforded 1.09 g of 2,6-dichloro-N′-hydroxybenzamidine (Yield: 76%)as beige powder (M.P.=163-164° C.).

55(B) 5-(But-3-ynyl)-3-(2,6-dichlorophenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 2,6-dichloro-N′-hydroxybenzamidine (697mg, 3.4 mmol) afforded 480 mg of5-(but-3-ynyl)-3-(2,6-dichlorophenyl)-1,2,4-oxadiazole (Yield: 53%) asyellow oil.

LCMS (RT): 3.89 min; MS (ES+) gave m/z: 267.0

55(C)2-(4-(3-(2,6-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(2,6-dichlorophenyl)-1,2,4-oxadiazole (480 mg, 1.8mmol) afforded 365 mg of2-(4-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 59%) as brown oil.

LCMS (RT): 3.73 min; MS (ES+) gave m/z: 344.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 7.63 (t, H), 7.45-7.36 (m, 4H), 7.22(t, H), 3.38 (t, 2H), 3.08 (t, 2H).

Example 562-(4-(3-(2,3-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine56(A) 2,3-Dichloro-N′-hydroxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2,3-dichlorobenzonitrile (1.20 g, 7mmol) afforded 1.36 g of 2,3-dichloro-N′-hydroxybenzamidine (Yield: 95%)as beige powder (M.P.=115-117° C.).

56(B) 5-(But-3-ynyl)-3-(2,3-dichlorophenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 2,3-dichloro-N′-hydroxybenzamidine (697mg, 3.4 mmol) afforded 374 mg of5-(but-3-ynyl)-3-(2,3-dichlorophenyl)-1,2,4-oxadiazole (Yield: 41%) asyellow oil.

LCMS (RT): 4.09 min; MS (ES+) gave m/z: 267.0

56(C)2-(4-(3-(2,3-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(2,3-dichlorophenyl)-1,2,4-oxadiazole (374 mg, 1.4mmol) afforded 193 mg of2-(4-(3-(2,3-dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 40%) as brown oil.

LCMS (RT): 3.91 min; MS (ES+) gave m/z: 346.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 7.81 (d, H), 7.66-7.61 (m, 2H), 7.38(d, H), 7.34 (t, H), 7.22 (t, H), 3.35 (t, 2H), 3.07 (t, 2H).

Example 572-(4-(3-(2,4-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine57(A) 2,4-Dichloro-N′-hydroxybenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2,4-dichlorobenzonitrile (1.20 g, 7mmol) afforded 1.40 g of 2,4-dichloro-N′-hydroxybenzamidine (Yield: 98%)as beige powder (M.P.=149-151° C.).

57(B) 5-(But-3-ynyl)-3-(2,4-dichlorophenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 2,4-dichloro-N′-hydroxybenzamidine (697mg, 3.4 mmol) afforded 553 mg of5-(but-3-ynyl)-3-(2,4-dichlorophenyl)-1,2,4-oxadiazole (Yield: 61%) asyellow oil.

LCMS (RT): 4.21 min; MS (ES+) gave m/z: 267.0

57(C)2-(4-(3-(2,4-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(2,4-dichlorophenyl)-1,2,4-oxadiazole (553 mg, 2.1mmol) afforded 430 mg of2-(4-(3-(2,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 59%) as beige powder (M.P.=77-78° C.).

LCMS (RT): 4.04 min; MS (ES+) gave m/z: 344.0

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 7.92 (d, H), 7.65 (t, H), 7.57 (d,H), 7.41-7.37 (m, 2H), 7.23 (t, H), 3.34 (t, 2H), 3.06 (t, 2H).

Example 582-(4-(3-(2-Chloro-6-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine58(A) 2-Chloro-N′-hydroxy-6-methylbenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-chloro-6-methylbenzonitrile (1.06 g,7 mmol) afforded 1.28 g of 2-chloro-N′-hydroxy-6-methylbenzamidine(Yield: 99%) as beige powder (M.P.=136-137° C.).

58(B) 5-(But-3-ynyl)-3-(2-chloro-6-methylphenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 2-chloro-N′-hydroxy-6-methylbenzamidine(628 mg, 3.4 mmol) afforded 458 mg of5-(but-3-ynyl)-3-(2-chloro-6-methylphenyl)-1,2,4-oxadiazole (Yield: 55%)as yellow oil.

LCMS (RT): 3.84 min; MS (ES+) gave m/z: no ionisation

58(C)2-(4-(3-(2-Chloro-6-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(2-chloro-6-methylphenyl)-1,2,4-oxadiazole (458 mg, 1.9mmol) afforded 420 mg of2-(4-(3-(2-chloro-6-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 68%) as brown oil.

LCMS (RT): 3.66 min; MS (ES+) gave m/z: 324.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 7.63 (t, H), 7.37 (d, H), 7.35-7.30(m, 2H), 7.24-7.18 (m, 2H), 3.36 (t, 2H), 3.08 (t, 2H), 2.22 (s, 3H).

Example 592-(4-(3-(5-Fluoro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine59(A) 5-Fluoro-N′-hydroxy-2-methylbenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 5-fluoro-2-methylbenzonitrile (0.95 g,7 mmol) afforded 1.27 g of 5-fluoro-N′-hydroxy-2-methylbenzamidine(Yield: 98%) as yellow oil.

59(B) 5-(But-3-ynyl)-3-(5-fluoro-2-methylphenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 5-fluoro-N′-hydroxy-2-methylbenzamidine(572 mg, 3.4 mmol) afforded 325 mg of5-(but-3-ynyl)-3-(5-fluoro-2-methylphenyl)-1,2,4-oxadiazole (Yield: 42%)as yellow oil.

LCMS (RT): 4.06 min; MS (ES+) gave m/z: 231.1

59(C)2-(4-(3-(5-Fluoro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(5-fluoro-2-methylphenyl)-1,2,4-oxadiazole (325 mg, 1.4mmol) afforded 190 mg of2-(4-(3-(5-fluoro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 44%) as beige powder (M.P.=90-91° C.).

LCMS (RT): 3.91 min; MS (ES+) gave m/z: 308.0

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 7.63 (t, H), 7.37 (d, H), 7.34-7.29(m, 2H), 7.24-7.18 (m, 2H), 3.36 (t, 2H), 3.08 (t, 2H), 2.22 (s, 3H).

Example 602-(4-(3-(5-Chloro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine60(A) 5-Chloro-N′-hydroxy-2-methylbenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 5-chloro-2-methylbenzonitrile (1.06 g,7 mmol) afforded 1.27 g of 5-chloro-N′-hydroxy-2-methylbenzamidine(Yield: 98%) as beige powder (M.P.=111-113° C.).

60(B) 5-(But-3-ynyl)-3-(5-chloro-2-methylphenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 5-chloro-N′-hydroxy-2-methylbenzamidine(628 mg, 3.4 mmol) afforded 376 mg of5-(but-3-ynyl)-3-(5-chloro-2-methylphenyl)-1,2,4-oxadiazole (Yield: 45%)as yellow oil.

LCMS (RT): 4.34 min; MS (ES+) gave m/z: 247.1

60(C)24443-(5-Chloro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(5-chloro-2-methylphenyl)-1,2,4-oxadiazole (376 mg, 1.5mmol) afforded 310 mg of2-(4-(3-(5-chloro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 64%) as beige powder (M.P.=66-68° C.).

LCMS (RT): 4.16 min; MS (ES+) gave m/z: 324.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 8.02 (d, H), 7.63 (t, H), 7.40 (d,H), 7.35 (d, H), 7.28-7.21 (m, 2H), 3.33 (t, 2H), 3.07 (t, 2H), 2.60 (s,3H).

Example 612-(4-(3-(2-(Trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine61(A) N′-Hydroxy-2-(trifluoromethoxy)benzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 2-(trifluoromethoxy)benzonitrile (1.31g, 7 mmol) afforded 1.55 g of N′-hydroxy-2-(trifluoromethoxy)benzamidine(Yield: 96%) as beige powder (M.P.=95-97° C.).

61(B) 5-(But-3-ynyl)-3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion ofN′-hydroxy-2-(trifluoromethoxy)benzamidine (749 mg, 3.4 mmol) afforded303 mg of 5-(but-3-ynyl)-3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole(Yield: 32%) as yellow oil.

LCMS (RT): 4.03 min; MS (ES+) gave m/z: 263.1

61(C)2-(4-(3-(2-(Trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (303 mg,1.1 mmol) afforded 213 mg of2-(4-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield: 54%) as brown oil.

LCMS (RT): 3.84 min; MS (ES+) gave m/z: 360.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 8.11 (d, H), 7.63 (t, H), 7.56 (t,H), 7.48-7.42 (m, 2H), 7.37 (d, H), 7.23 (t, H), 3.33 (t, 2H), 3.07 (t,2H).

Example 62 6-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 62(A)2-Amino-5-fluorophenol

A suspension of 3-fluoro-6-nitrophenol (500 mg, 3.18 mmol) and zinc(2.10 g, 31.8 mmol) in acetic acid (7.3 mL) was stirred overnight atroom temperature. The reaction mixture was filtered through celite andwashed with DCM. After evaporation and distillation under vacuum (2.10⁻²mbar) of the solvents, the residue was dissolved in DCM. The organicphase was washed with a saturated solution of NaHCO₃ and brine, driedover MgSO₄, filtered and evaporated. The crude residue was purified byflash chromatography (DCM/MeOH 99.5:0.5) to yield 177 mg (1.39 mmol,44%) of 2-amino-5-fluorophenol as an orange solid.

62(B) 2-(But-3-ynyl)-6-fluorobenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-5-fluorophenol (177 mg, 1.39 mmol). Reactiontime: 3 days. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 47 mg (0.25 mmol, 18%) of2-(but-3-ynyl)-6-fluorobenzo[d]oxazole.

62(C) 6-Fluoro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (39 mg, 0.25 mmol) and2-(but-3-ynyl)-6-fluorobenzo[d]oxazole (47 mg, 0.25 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1) to yield 21mg (78 mmol, 31%) of6-fluoro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid.

LCMS (RT): 3.04 min; MS (ES+) gave m/z: 267.0.

¹H-NMR (CDCl₃), δ (ppm): 3.05 (t, J=7.5, 2H), 3.28 (t, J=7.5, 2H),7.04-7.09 (m, 1H), 7.18-7.22 (m, 1H), 7.23 (dd, J=2.5 and 8.0, 1H), 7.35(d, J=2.5, 1H), 7.59-7.63 (2H), 8.53-8.56 (m, 1H).

Example 63 7-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 63(A)2-Amino-6-chlorophenol

The title compound was prepared in accordance with the general method ofExample 62(A), from 6-chloro-2-nitrophenol (500 mg, 2.88 mmol). Thecrude residue was purified by flash chromatography (DCM/MeOH 99.5:0.5)to yield 73 mg (0.51 mmol, 18%) of 2-amino-6-chlorophenol.

63(B) 2-(But-3-ynyl)-7-chlorobenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-6-chlorophenol (73 mg, 0.51 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 9:1) toyield 42 mg (0.20 mmol, 40%) of 2-(but-3-ynyl)-7-chlorobenzo[d]oxazole.

63(C) 7-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (32 mg, 0.20 mmol) and2-(but-3-ynyl)-7-chlorobenzo[d]oxazole (42 mg, 0.20 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1) to yield 25mg (90 μmol, 44%) of7-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil.

LCMS (RT): 3.44 min; MS (ES+) gave m/z: 283.0, 285.0.

¹H-NMR (CDCl₃), δ (ppm): 3.08 (t, J=8.0, 2H), 3.33 (t, J=8.0, 2H),7.18-7.21 (m, 1H), 7.24-7.28 (m, 1H), 7.32 (dd, J=1.0 and 8.0, 1H),7.36-7.39 (m, 1H), 7.57-7.63 (2H), 8.53-8.55 (m, 1H).

Example 64 7-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 64(A)2-Amino-6-fluorophenol

The title compound was prepared in accordance with the general method ofExample 62(A), from 6-fluoro-2-nitrophenol (500 mg, 3.18 mmol). Thecrude residue was purified by flash chromatography (AcOEt/cyclohexane7:3) to yield 213 mg (1.68 mmol, 54%) of 2-amino-6-fluorophenol as abrown solid.

64(B) 2-(But-3-ynyl)-7-fluorobenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-6-fluorophenol (213 mg, 1.68 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 9:1) toyield 128 mg (0.68 mmol, 40%) of 2-(but-3-ynyl)-7-fluorobenzo[d]oxazole.

64(C) 7-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (107 mg, 0.68 mol) and2-(but-3-ynyl)-7-fluorobenzo[d]oxazole (128 mg, 0.68 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1) to yield 94mg (0.35 mmol, 52%) of7-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil.

LCMS (RT): 3.13 min; MS (ES+) gave m/z: 267.1.

¹H-NMR (CDCl₃), δ (ppm): 3.08 (t, J=7.0, 2H), 3.32 (t, J=7.0, 2H),7.05-7.10 (m, 1H), 7.18-7.21 (m, 1H), 7.23-7.28 (m, 1H), 7.36-7.38 (m,1H), 7.48 (dd, J=1.0 and 8.0, 1H), 7.59-7.63 (m, 1H), 8.53-8.55 (m, 1H).

Example 65 2-(4-(5-Phenyloxazol-2-yl)but-1-ynyl)pyridine 65(A)N-(2-Hydroxy-2-phenylethyl)pent-4-ynamide

To a solution of pent-4-ynoic acid (1.00 g, 10.2 mmol) in dry DCM (10mL) was added at room temperature oxalyl chloride (1.75 mL, 20.0 mmol)and some drops of DMF. The reaction mixture was stirred for 2 hoursandwas concentrated to dryness to yield pent-4-ynoyl chloride which wasused without further purification. A solution of 390 mg (3.35 mmol) ofpent-4-ynoyl chloride in dry DCM (5 mL) was added slowly to a solutionof 2-amino-1-phenylethanol (480 mg, 3.30 mmol) and triethylamine (0.93mL, 6.69 mmol) in dry DCM (10 mL). The reaction mixture was stirred for20 min. at room temperature. After evaporation of the solvent, the crudeproduct was dissolved in DCM. The organic phase was washed with asaturated solution of NaHCO₃, brine, dried over MgSO₄, filtered andconcentrated to lead in a quantitative yield to 727 mg (3.35 mmol) ofN-(2-hydroxy-2-phenylethyl)pent-4-ynamide.

65(B) Pent-4-ynoic acid (2-oxo-2-phenyl-ethyl)-amide

169 mg (0.78 mmol) of N-(2-hydroxy-2-phenylethyl)pent-4-ynamide in DCM(1 mL) were added to a solution of PCC (326 mg, 1.48 mmol) in DCM (4mL). The reaction mixture was stirred for 4 hours at room temperature,dissolved in DCM and then quenched with NaOH 1N. The organic phase waswashed with brine, dried over MgSO₄, filtered and concentrated to yield160 mg (0.74 mmol, 95%) of pent-4-ynoic acid(2-oxo-2-phenyl-ethyl)-amide as a yellow solid.

65(C) 2-(But-3-ynyl)-5-phenyloxazole

907 mg (6.39 mmol) of P₂O₅ were added to a solution of pent-4-ynoic acid(2-oxo-2-phenyl-ethyl)-amide (160 mg, 0.74 mmol) in POCl₃ (10.4 mL). Thereaction mixture was stirred for 2 hours at 105° C. and then pouredcarefully onto ice. The solution was basified with NaOH 1N followed byNaOH pellets till pH=8. The aqueous phase was extracted thrice with DCM.The organic phase was washed with brine, dried over MgSO₄, filtered andevaporated. The crude residue was purified by flash chromatography(DCM/MeOH 99:1) to yield 31 mg (0.16 mmol, 21%) of2-(but-3-ynyl)-5-phenyloxazole as an orange oil.

65(D) 2-(4-(5-Phenyloxazol-2-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (25 mg, 0.16 mmol) and2-(but-3-ynyl)-5-phenyloxazole (31 mg, 0.16 mmol). The crude residue waspurified by flash chromatography (DCM/MeOH 99:1) and SCX column(DCM/MeOH 95:5, DCM/MeOH/NH₄OH 90:5:0.1 to 90:9:1) to yield 4.0 mg (15μmol, 9%) of 2-(4-(5-phenyloxazol-2-yl)but-1-ynyl)pyridine as a yellowoil.

LCMS (RT): 3.33 min; MS (ES+) gave m/z: 275.1.

Example 662-(4-(3-(3-Chloro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine66(A) 3-Chloro-N′-hydroxy-2-methylbenzamidine

According to the general protocol for amidoxime synthesis described inExample 15(A), the conversion of 3-chloro-2-methylbenzonitrile (1.06 g,7 mmol) afforded 1.28 g of 3-chloro-N′-hydroxy-2-methylbenzamidine(Yield: 99%) as beige powder (M.P.=119-121° C.).

66(B) 5-(But-3-ynyl)-3-(3-chloro-2-methylphenyl)-1,2,4-oxadiazole

According to the general protocol for oxadiazole synthesis described inExample 40(B), the conversion of 3-chloro-N′-hydroxy-2-methylbenzamidine(628 mg, 3.4 mmol) afforded 387 mg of5-(but-3-ynyl)-3-(3-chloro-2-methylphenyl)-1,2,4-oxadiazole (Yield: 46%)as yellow oil.

LCMS (RT): 4.26 min; MS (ES+) gave m/z: 247.1

66(C)2-(4-(3-(3-Chloro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of5-(but-3-ynyl)-3-(3-chloro-2-methylphenyl)-1,2,4-oxadiazole (628 mg, 3.4mmol) afforded 387 mg of2-(4-(3-(3-chloro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine(Yield 46%) as brown oil.

LCMS (RT): 4.08 min; MS (ES+) gave m/z: 324.1

¹NMR (CDCl₃), δ (ppm): 8.64 (s, H), 7.79 (d, H), 7.64 (t, H), 7.52 (d,H), 7.38 (d, H), 7.28-7.20 (m, 2H), 3.34 (t, 2H), 3.07 (t, 2H), 2.64 (s,3H).

Example 678-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 67(A)Ethyl 8-methyl-imidazo[1,2-a]pyridine-2-carboxylate

According to the general protocol as described in Example 33(A), theconversion of 3-methylpyridin-2-amine (2.3 g, 21 mmol) afforded 2.97 gof ethyl 8-methyl-imidazo[1,2-a]pyridine-2-carboxylate (Yield: 69%) as ared solid. Purification over silicagel chromatography (DCM/MeOH from100/0 to 97/3 as eluent).

LCMS (RT): 0.72-1.77 min; MS (ES+) gave m/z: 205.1

Rf (DCM/MeOH: 98/2): 0.22

djg 15@cam.ac.uk

67(B) (8-Methyl-imidazo[1,2-a]pyridin-2-yl)methanol

According to the general protocol as described in Example 33(B), theconversion of ethyl 8-methyl-imidazo[1,2-a]pyridine-2-carboxylate (2.97g, 14.5 mmol) afforded 1.17 g of(8-methyl-imidazo[1,2-a]pyridin-2-yl)methanol (Yield: 50%) as a orangeoil. Purification over silicagel chromatography (prepacked 70 gsilicagel column, DCM/MeOH from 100/0 to 95/5 as eluent).

LCMS (RT): 0.67 min; MS (ES+) gave m/z: 163.1

Rf (DCM/MeOH: 95/5): 0.10

67(C) 2-(Chloromethyl)-8-methyl-imidazo[1,2-a]pyridine

According to the general protocol as described in Example 33(C), theconversion of (8-methyl-imidazo[1,2-a]pyridin-2-yl)methanol (1.17 g,7.21 mmol) afforded 1.23 g of2-(chloromethyl)-8-methyl-imidazo[1,2-a]pyridine (Yield: 94%) as abrownish solid (M.P.: 115.4-116.8° C.).

LCMS (RT): 0.64-1.05 min; MS (ES+) gave m/z: 181.1

Rf (DCM/MeOH: 95/5): 0.27

67(D) 8-Methyl-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine

To a solution of trimethyl(prop-1-ynyl)silane (259 mg, 2.31 mmol) in THF(7.5 mL) at −78° C. was added n-BuLi 2.5M in hexane (1.1 mL, 2.8 mmol).After 90 min at −78° C. 2-(chloromethyl)-8-methyl-imidazo[1,2-a]pyridine(500 mg, 2.8 mmol) in THF (5 mL) was added dropwise. The solution becameblue-green at −78° C. The solution was stirred at −78° C. for anadditional 1 h. The reaction was quenched with water and the solvent wasremoved under reduced pressure. The crude product was purified oversilicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH from100/0 to 99/1 as eluent) to afford 590 mg of8-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:100%) as an yellow oil.

LCMS (RT): 0.59-2.61 min; MS (ES+) gave m/z: 257.1

Rf (DCM/MeOH:95/5): 0.22

67(E) 2-(But-3-ynyl)-8-methyl-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(D), the conversion of8-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (590mg, 2.30 mmol) afforded 424 mg of2-(but-3-ynyl)-8-methyl-imidazo[1,2-a]pyridine (Yield: 100%) as yellowoil. Purification over silicagel chromatography (prepacked 25 gsilicagel column, DCM/MeOH: 95/5 as eluent).

LCMS (RT): 2.89 min; MS (ES+) gave m/z: 265.1

67(F) 8-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of2-(but-3-ynyl)-8-methyl-imidazo[1,2-a]pyridine (100 mg, 0.54 mmol)afforded 114 mg of8-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:80%) as yellow oil.

Purification over silicagel chromatography (prepacked 10 g silicagelcolumn, DCM/MeOH: 97/3 as eluent).

LCMS (RT): 2.16 min; MS (ES+) gave m/z: 262.1

Rf (DCM/MeOH: 95/5): 0.33

¹H-NMR (CDCl₃), δ (ppm): 8.54 (d, H), 7.98 (d, H), 7.62 (t, H), 7.55 (s,H), 7.36 (d, H), 7.18 (m, H), 7.00 (d, H), 6.72 (t, H), 3.20 (t, 2H),2.94 (t, 2H), 2.64 (s, 3H).

Example 685-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 68(A)Ethyl 5-methyl-imidazo[1,2-a]pyridine-2-carboxylate

According to the general protocol as described in Example 33(A), theconversion of 6-methylpyridin-2-amine (2.3 g, 21 mmol) afforded 2.59 gof ethyl 5-methyl-imidazo[1,2-a]pyridine-2-carboxylate (Yield: 60%) as abrownish solid. Purification over silicagel chromatography (DCM/MeOHfrom 100/0 to 97/3 as eluent).

LCMS (RT): 0.72-1.49 min; MS (ES+) gave m/z: 205.1

Rf (DCM/MeOH: 98/2): 0.22

68(B) (5-Methyl-imidazo[1,2-a]pyridin-2-yl)methanol

According to the general protocol as described in Example 33(B), theconversion of ethyl 5-methyl-imidazo[1,2-a]pyridine-2-carboxylate (2.59g, 12.7 mmol) afforded 1.58 g of(5-methyl-imidazo[1,2-a]pyridin-2-yl)methanol (Yield: 77%) as ayellowish solid. Purification over silicagel chromatography (prepacked70 g silicagel column, DCM/MeOH from 100/0 to 95/5 as eluent).

LCMS (RT): 0.67 min; MS (ES+) gave m/z: 163.1

Rf (DCM/MeOH:95/5): 0.32

68(C) 2-(Chloromethyl)-5-methyl-imidazo[1,2-a]pyridine

According to the general protocol as described in Example 33(C), theconversion of (5-methyl-imidazo[1,2-a]pyridin-2-yl)methanol (1.58 g,9.74 mmol) afforded 1.67 g of2-(chloromethyl)-5-methyl-imidazo[1,2-a]pyridine (Yield: 95%) as a beigesolid (M.P.: 120-120.6° C.).

LCMS (RT): 0.64-1.05 min; MS (ES+) gave m/z: 181.1

Rf (DCM/MeOH: 95/5): 0.27

68(D) 5-Methyl-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine

According to the general protocol as described in Example 67(D), theconversion of 2-(chloromethyl)-5-methyl-imidazo[1,2-a]pyridine (500 mg,2.80 mmol) afforded 525 mg of5-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:89%) as an yellow oil. Purification over silicagel chromatography(prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 99/1 aseluent).

LCMS (RT): 0.59-2.59 min; MS (ES+) gave m/z: 257.1

Rf (DCM/MeOH: 95/5): 0.19

68(E) 2-(But-3-ynyl)-5-methyl-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(D), the conversion of5-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (525mg, 2.04 mmol) afforded 352 mg of2-(but-3-ynyl)-5-methyl-imidazo[1,2-a]pyridine (Yield: 93%) as yellowoil. Purification over silicagel chromatography (prepacked 25 gsilicagel column, DCM/MeOH: 95/5 as eluent).

LCMS (RT): 2.89 min; MS (ES+) gave m/z: 265.1

68(F) 5-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of2-(but-3-ynyl)-5-methyl-imidazo[1,2-a]pyridine (100 mg, 0.54 mmol)afforded 78 mg of5-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:55%) as yellow oil. Purification over silicagel chromatography(prepacked 10 g silicagel column, DCM/MeOH:97/3 as eluent).

LCMS (RT): 2.19 min; MS (ES+) gave m/z: 262.1

Rf (DCM/MeOH:95/5): 0.30

¹H-NMR (CDCl₃), δ (ppm): 8.54 (d, H), 7.61 (t, H), 7.53 (d, H), 7.44 (s,H), 7.37 (d, H), 7.22-7.15 (m, 2H), 6.65 (d, H), 3.20 (t, 2H), 2.95 (t,2H), 2.59 (s, 3H).

Example 695-Phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 69(A)Ethyl 5-bromo-imidazo[1,2-a]pyridine-2-carboxylate

According to the general protocol as described in Example 33(A), theconversion of 6-bromopyridin-2-amine (3.6 g, 21 mmol) afforded 4.70 g ofethyl 5-bromo-imidazo[1,2-a]pyridine-2-carboxylate (Yield: 83%) as ayellow solid. Purification over silicagel chromatography (DCM/MeOH from100/0 to 97/3 as eluent).

LCMS (RT): 2.87 min; MS (ES+) gave m/z: 270.1

Rf (DCM/MeOH: 98/2): 0.22

69(B) Ethyl 5-phenyl-imidazo[1,2-a]pyridine-2-carboxylate

To a suspension of ethyl 5-bromo-imidazo[1,2-a]pyridine-2-carboxylate(1.50 g, 5.6 mmol), Pd(PPh₃)₄ (322 mg, 0.279 mmol) in a mixture oftoluene (17 mL), NaHCO₃ 1M (6 mL) and MeOH (4 mL) was addedphenylboronic acid at room temperature. The resulting reaction mixturewas heated at 80° C. for 12 h, cooled, and diluted with water (50 mL).The insoluble matter was filtered off, and the phases were separated.The aqueous phase was extracted with ethyl acetate, the combined organiclayers were washed with water and the solvent was removed under reducedpressure. The crude product was purified by chromatography (prepacked 25g silicagel column, DCM/MeOH from 100/0 to 99/1 as eluent) to afford1.41 g of ethyl 5-phenyl-imidazo[1,2-a]pyridine-2-carboxylate (Yield:95%) as a yellowish solid (M.P.: 123-123.8° C.)

LCMS (RT): 3.06 min; MS (ES+) gave m/z: 266.1

Rf (DCM/MeOH:98/2): 0.18

69(C) (5-Phenyl-imidazo[1,2-a]pyridin-2-yl)methanol

According to the general protocol as described in Example 33(B), theconversion of ethyl 5-phenyl-imidazo[1,2-a]pyridine-2-carboxylate (1.40g, 5.26 mmol) afforded 538 mg of(5-phenyl-imidazo[1,2-a]pyridin-2-yl)methanol (Yield: 45%) as an orangeoil. Purification over silicagel chromatography (prepacked 25 gsilicagel column, DCM/MeOH from 100/0 to 98/2 as eluent).

LCMS (RT): 0.65-1.77 min; MS (ES+) gave m/z: 225.1

Rf (DCM/MeOH:90/10): 0.28

69(D) 2-(Chloromethyl)-5-phenyl-imidazo[1,2-a]pyridine

According to the general protocol as described in Example 33(C), theconversion of (5-phenyl-imidazo[1,2-a]pyridin-2-yl)methanol (538 mg,2.40 mmol) afforded 555 mg of2-(chloromethyl)-5-phenyl-imidazo[1,2-a]pyridine (Yield: 95%) as a beigesolid (M.P.: 125.8-126.6° C.).

LCMS (RT): 0.65-2.31 min; MS (ES+) gave m/z: 243.1

Rf (DCM/MeOH: 90/10): 0.31

69(E) 2-(4-(Trimethylsilyl)but-3-ynyl)-5-phenyl-imidazo[1,2-a]pyridine

According to the general protocol as described in Example 67(D), theconversion of 2-(chloromethyl)-5-phenyl-imidazo[1,2-a]pyridine (500 mg,2.10 mmol) afforded 543 mg of2-(4-(trimethylsilyl)but-3-ynyl)-5-phenyl-imidazo[1,2-a]pyridine (Yield:99%) as an yellow oil Purification over silicagel chromatography(prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 99/1 aseluent).

LCMS (RT): 3.08 min; MS (ES+) gave m/z: 319.1

Rf (DCM/MeOH: 95/5): 0.31

69(F) 2-(But-3-ynyl)-5-phenyl-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(D), the conversion of2-(4-(trimethylsilyl)but-3-ynyl)-5-phenyl-imidazo[1,2-a]pyridine (500mg, 1.90 mmol) afforded 350 mg of2-(but-3-ynyl)-5-phenyl-imidazo[1,2-a]pyridine (Yield: 97%) as yellowoil. Purification over silicagel chromatography (prepacked 25 gsilicagel column, DCM/MeOH: 95/5 as eluent).

LCMS (RT): 2.89 min; MS (ES+) gave m/z: 265.1

69(G) 5-Phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

According to the general protocol for Sonogashira coupling described inExample 15(C), the conversion of2-(but-3-ynyl)-5-phenyl-imidazo[1,2-a]pyridine (100 mg, 0.40 mmol)afforded 100 mg of5-phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:76%) as yellow oil. Purification over silicagel chromatography(prepacked 10 g silicagel column, DCM/MeOH: 97/3 as eluent).

LCMS (RT): 2.84 min; MS (ES+) gave m/z: 324.1

Rf (DCM/MeOH: 95/5): 0.30

¹H-NMR (CDCl₃), δ (ppm): 8.54 (d, H), 7.61-7.65 (m, 2H), 7.61-7.57 (m,3H), 7.52-7.48 (m, 3H), 7.32-7.24 (m, 2H), 7.18 (m, H), 6.74 (d, H),3.12 (t, 2H), 2.90 (t, 2H).

Example 70 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-4-ol 70(A)2-Aminobenzene-1,3-diol

The title compound was prepared in accordance with the general method ofExample 62(A), from 2-nitrobenzene-1,3-diol (1.37 g, 8.81 mmol). 1.10 g(8.81 mmol, 100%) of 2-aminobenzene-1,3-diol were obtained as an orangesolid and used without purification.

70(B) 2-(But-3-ynyl)benzo[d]oxazol-4-ol

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-aminobenzene-1,3-diol (272 mg, 2.17 mmol). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt9:1) to yield 241 mg (1.29 mmol, 60%) of2-(but-3-ynyl)benzo[d]oxazol-4-ol as an orange solid.

70(C) 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-4-ol

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (203 mg, 1.29 mol) and2-(but-3-ynyl)benzo[d]oxazol-4-ol (241 mg, 1.29 mmol). The crude residuewas purified by flash chromatography (DCM/MeOH 99:1 to 98:2) and SCXcolumn (DCM/MeOH 100:0 to 94:6, DCM/MeOH/NH₄OH 94:5:1 to 90:8:2) toyield 25 mg (95 mmol, 7%) of2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-4-ol as an orange solid.

LCMS (RT): 3.26 min; MS (ES+) gave m/z: 265.0.

Rf (DCM/MeOH 98:2)=0.04.

Example 71 2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-5-fluoropyridine (200 mg, 1.14 mol) and2-(but-3-ynyl)benzo[d]oxazole (195 mg, 1.14 mmol, Example 8(A)). Thecrude residue was purified by flash chromatography (DCM/MeOH 99:1) andSCX column (DCM/MeOH 100:0 to 94:6, DCM/MeOH/NH₄OH 94:5:1 to 90:8:2) toyield 15 mg (56 mmol, 5%) of2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a white solid.

LCMS (RT): 4.19 min; MS (ES+) gave m/z: 267.0.

Example 72 4-Methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

A mixture of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-4-ol (20 mg,76 μmol, Example 70), methyl iodide (57 μL, 114 μmol) and K₂CO₃ (18 mg,130 μmol) in DMF (2 mL) was stirred under reflux for 3 h. The reactionmixture was then allowed to cool to room temperature and was dissolvedin DCM. The organic phase was washed with water, HCl 1N, saturatedsolution of NaHCO₃, brine, dried over MgSO₄, filtered and evaporated.The crude residue was purified by flash chromatography (DCM/MeOH 99:1)to yield 10 mg (36 mmol, 47%) of4-methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brownsolid.

LCMS (RT): 3.69 min; MS (ES+) gave m/z: 279.1.

Example 73 2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)imidazo[1,2-a]pyridine73(A) 4-Bromo-2-methylthiazole

To a solution of 2,4-Dibromothiazole (5.00 g, 20.6 mmol) in anhydrousDiethyl ether (70 mL) was added dropwise at −78° C., 11 mL of BuLi 2.5Min hexane. The mixture was stirred for 2 h at −78° C. A solution ofmethyl trifluoromethanesulfonate (3.38 g, 20.6 mmol) in 10 mL of Diethylether was added dropwise at −78° C. to the resulting mixture. After 30min of stiffing at −78° C., the reaction mixture was slowly warmed toroom temperature for 2 h. The reaction was cooled with a ice bath at−10° C. and quenched with water. The layers were separated; the aqueouslayer was extracted with Diethyl ether. The combined organic layers weredried over Na₂SO₄, filtered and concentrated under medium pressure 700mbar, bath 35° C., because the bromothiazole is very volatil. The crudeproduct was purified by flash chromatography (Prepacked 70 g silicagelcolumn with Pentane/Diethyl ether: 95/5 as eluent) to afford 2 g of4-bromo-2-methylthiazole (Yield: 54%) as a yellow oil.

Rf (Pentane/Diethyl ether 95/5): 0.30

LCMS (RT): 3.33 min; MS (ES+) gave m/z: 179.0

73(B) 4-Iodo-2-methylthiazole

To a solution of 4-bromo-2-methylthiazole (2.0 g, 11 mmol) in anhydrousDiethyl ether (44 mL) was added dropwise at −78° C., 5.30 mL of BuLi2.5M in hexane. The mixture was stirred for 1 h at −78° C. A solution ofdiiodoethane (6.20 g, 22 mmol) in 27 mL of Diethyl ether was addeddropwise at −78° C. to the reaction mixture. The resulting solution wasstirred 30 min at −78° C. and slowly warmed to room temperature over aperiod of 2 h. The reaction cooled with a ice bath at −10° C. andquenched with water. The two layers were separated; the aqueous layerwas extracted with Diethyl ether. The combined organic layers were driedover Na₂SO₄, filtered and concentrated under medium pressure. The crudeproduct was purified by flash chromatography (Prepacked 10 g silicagelcolumn with Pentane/Diethyl ether: 95/5 as eluent) to afford 1.17 g of4-iodo-2-methylthiazole (Yield: 47%) as a colorless oil.

LCMS (RT): 3.49 min; MS (ES+) gave m/z: 225.0

73(C) 2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

In a dry reaction tube containing in suspension copper iodide (6.5 mg,0.03 mmol) and triethylamine (2.33 mL, 13.60 mmol), were added4-iodo-2-methylthiazole (150 mg, 0.68 mmol) and Pd(PPh₃)₂Cl₂ (39 mg,0.03 mmol) under N₂. A yellow suspension is obtained and after a fewminutes of stiffing at room temperature, was added a solution2-(but-3-ynyl)-imidazo[1,2-a]pyridine (115 mg, 0.68 mmol) intriethylamine (0.5 mL) under N₂. Immediately the color of the reactionturns to black. The mixture was stirred at room temperature for 4 h and50° C. overnight under N₂. Triethylamine was removed under reducepressure. The crude product was purified by flash chromatography(Prepacked 25 g silicagel column from DCM/MeOH: 100/0 to 97/3 as eluent)to afford 25 mg of2-(4-(2-methylthiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:14%) as a yellow oil.

Rf (DCM/MeOH: 95/5): 0.50

LCMS (RT): 0.79-2.38 min; MS (ES+) gave m/z: 268.0

¹H-NMR (CDCl₃), δ (ppm): 8.09 (d, H), 7.66 (d, H), 7.52 (s, H),7.23-7.18 (m, 2H), 6.81 (t, H), 3.14 (t, 2H), 2.92 (t, 2H), 2.70 (s,3H).

Example 746-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 74(A)2-(Chloromethyl)-6-fluoro-imidazo[1,2-a]pyridine

According to the general protocol described in J. Heterocyclic. Chem.,1988, 25, 129-137, to solution of 5-fluoropyridin-2-amine (1.80 g, 16mmol) in EtOH (24 mL) was added 1,3-dichloropropan-2-one (2.03 g, 16mmol) and the resulting mixture was stirred overnight at 80° C. Thesolvent was evaporated, and the residue was dissolved in a minimumvolume of water. The solution was neutralized (pH=8) with saturatedNaHCO₃. The aqueous layer was extracted with AcOEt and the organic layerwas washed with saturated NaCl. The solvent was evaporated and the crudeproduct was purified by chromatography (prepacked 25 g silicagel column,DCM as eluent) to afford 1.7 g of2-(chloromethyl)-6-fluoro-imidazo[1,2-a]pyridine

(Yield: 57%) as a beige solid.

LCMS (RT): 0.88-1.68 min; MS (ES+) gave m/z: 185.0

Rf (DCM/MeOH: 98/2): 0.50

74(B) 6-Fluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine

According to the general protocol as described in Example 38(C), theconversion of 2-(chloromethyl)-6-fluoro-imidazo[1,2-a]pyridine (1.70 g,9.1 mmol) afforded 496 mg of6-fluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:25%) as white powder. Purification over silicagel chromatography(prepacked 25 g silicagel column, Cyclohexane/AcOEt from 70/30 to 60/40as eluent).

LCMS (RT): 3.01 min; MS (ES+) gave m/z: 261.0

Rf (Cyclohexane/AcOEt:50/50): 0.50

74(C) 2-(But-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(D), the conversion of6-fluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (490mg, 1.90 mmol) afforded 333 mg of2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (Yield: 93%) as yellowoil. Purification over silicagel chromatography (prepacked 25 gsilicagel column, DCM/MeOH: 98/2 as eluent).

LCMS (RT): 0.79 min; MS (ES+) gave m/z: 189.0

Rf (DCM/MeOH: 98/2): 0.30

74(D) 6-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

According to the general protocol for Sonogashira coupling described inExample 40(C), the conversion of2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (331 mg, 1.76 mmol)afforded 230 mg of6-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield49%) as yellow oil. Purification over silicagel chromatography(prepacked 25 g silicagel column, DCM/MeOH: from 100/0 to 97/3 aseluent).

LCMS (RT): 0.79-2.06 min; MS (ES+) gave m/z: 266.0

Rf (DCM/MeOH: 95/5): 0.50

¹H-NMR (CDCl₃), δ (ppm): 8.54 (d, H), 8.01 (m, H), 7.62 (m, H),7.56-7.51 (m, 2H), 7.37 (d, H), 7.22-7.18 (m, H), 7.07 (m, H), 3.14 (t,2H), 2.92 (t, 2H).

Example 75 2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine75(A) 2-(Chloromethyl)-imidazo[1,2-a]pyridine

According to the general described in Example 74(A), the conversion of2-aminopyridine (4.90 g, 52 mmol) afforded 2.66 g of2-(chloromethyl)-imidazo[1,2-a]pyridine (Yield 40%) as yellowsemi-solid. Purification over silicagel chromatography (prepacked 70 gsilicagel column, DCM as eluent).

LCMS (RT): 0.81 min; MS (ES+) gave m/z: 167.0

Rf (DCM/MeOH: 98/2): 0.50

75(B) 2-(4-(Trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(C), the conversion of2-(chloromethyl)-imidazo[1,2-a]pyridine (2.50 g, 15 mmol) afforded 555mg of 2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:15%) as yellow oil. Purification over silicagel chromatography(prepacked 70 g silicagel column, Cyclohexane/AcOEt from 60/40 to 50/50as eluent).

LCMS (RT): 3.00 min; MS (ES+) gave m/z: 243.0

Rf (Cyclohexane/AcOEt:50/50): 0.30

75(C) 2-(But-3-ynyl)-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(D), the conversion of2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (555 mg, 2.29mmol) afforded 352 mg of 2-(but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:90%) as yellow oil. Purification over silicagel chromatography(prepacked 25 g silicagel column, DCM/MeOH from 98/2 as eluent).

LCMS (RT): 2.84 min; MS (ES+) gave m/z: 171.0

Rf (DCM/MeOH: 98/2): 0.30

75(D) 2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

In a dry reaction tube containing in suspension copper iodide (6.5 mg,0.03 mmol) and triethylamine (2.3 mL), were added2-bromo-5-fluoropyridine (120 mg, 0.68 mmol) and Pd(PPh₃)₂Cl₂ (39 mg,0.03 mmol) under N₂. A yellow suspension was obtained after 5 min ofstiffing at room temperature. A solution of2-(but-3-ynyl)-imidazo[1,2-a]pyridine (120 mg, 0.68 mmol) intriethylamine (0.5 mL) was then added under N₂. Immediately the color ofthe reaction turns to black. The mixture was stirred at room temperaturefor 30 min and heated at 80° C. overnight. The reaction mixture wasconcentrated and the crude product was purified by Flash chromatography(prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 97/3 as eluent)to afford 15 mg of2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:8%) as a brown semi-solid.

Rf (DCM/MeOH: 95/5)=0.5.

LCMS (RT): 0.79-2.38 min; MS (ES+) gave m/z: 266.0

¹H-NMR (CDCl₃), δ (ppm): 8.40 (d, H), 8.08 (d, H), 7.63-7.58 (m, H),7.42-7.38 (m, 2H), 7.36-7.31 (m, H), 7.17 (t, H), 6.77 (m, H), 3.14 (t,2H), 2.92 (t, 2H).

Example 76 2-(4-(Pyridin-2-yl)but-3-ynyl)oxazolo[5,4-b]pyridine 76(A)2-(But-3-ynyl)oxazolo[5,4-b]pyridine

The title compound was prepared in accordance with the general method ofExample 8(A), from 3-aminopyridin-2-ol (449 mg, 4.08 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 7:3) toyield 500 mg (2.90 mmol, 71%) of 2-(but-3-ynyl)oxazolo[5,4-b]pyridine.

LCMS (RT): 3.16 min; MS (ES+) gave m/z: 173.0.

76(B) 2-(4-(Pyridin-2-yl)but-3-ynyl)oxazolo[5,4-b]pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (92 mg, 0.58 mmol) and2-(but-3-ynyl)oxazolo[5,4-b]pyridine (100 mg, 0.58 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 98.5:1.5 to 98:2)to yield 56 mg (0.22 mmol, 39%) of2-(4-(pyridin-2-yl)but-3-ynyl)oxazolo[5,4-b]pyridine as a colorless oil.

LCMS (RT): 2.91 min; MS (ES+) gave m/z: 250.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.08 (t, J=7.5, 2H), 3.33 (t, J=7.5, 2H),7.17-7.21 (m, 1H), 7.31 (dd, J=5.0 and 8.0, 1H), 7.34-7.38 (m, 1H),7.58-7.62 (m, 1H), 8.00 (dd, J=1.5 and 8.0, 1H), 8.32 (dd, J=1.5 and4.5, 1H), 8.53-8.54 (d, J=4.5, 1H).

Example 777-Chloro-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 77(A)2-Chloro-4-fluoro-6-nitrophenol

2-Chloro-4-fluorophenol (5.64 g, 38.5 mmol) was added to a solution ofacetic acid (16.5 mL), nitric acid (8.66 mL) and water (7.5 mL) at 0° C.The reaction mixture was stirred vigorously for 5 hours at 0° C. Theresulting precipitate was filtered, washed with water and dried undervacuum to yield 2-chloro-4-fluoro-6-nitrophenol (6.12 g, 32.0 mmol, 83%)as a yellow powder.

77(B) 2-Amino-6-chloro-4-fluorophenol

The title compound was prepared in accordance with the general method ofExample 62(A), from 2-chloro-4-fluoro-6-nitrophenol (6.12 g, 32.0 mmol).The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 1.66 g (10.3 mmol, 29%) of2-amino-6-chloro-4-fluorophenol.

77(C) 2-(But-3-ynyl)-7-chloro-5-fluorobenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-6-chloro-4-fluorophenol (1.66 g, 10.3 mmol).The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 690 mg (3.08 mmol, 30%) of2-(but-3-ynyl)-7-chloro-5-fluorobenzo[d]oxazole.

77(D) 7-Chloro-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (141 mg, 0.89 mmol) and2-(but-3-ynyl)-7-chloro-5-fluorobenzo[d]oxazole (200 mg, 0.89 mmol). Thecrude residue was purified by flash chromatography (DCM/MeOH 99:1) toyield 160 mg (0.53 mmol, 59%) of7-chloro-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as anorange solid.

LCMS (RT): 4.38 min; MS (ES+) gave m/z: 301.1, 303.0.

¹H-NMR (CDCl₃), δ (ppm): 3.07 (t, J=7.5, 2H), 3.32 (t, J=7.5, 2H), 7.11(dd, J=2.4 and 9.3, 1H), 7.17-7.24 (m, 1H), 7.30 (dd, J=2.4 and 8.1,1H), 7.37 (d, J=8.1, 1H), 7.58-7.66 (m, 1H), 8.54 (d, J=4.8, 1H).

Example 78 2-(4-(Pyridin-2-yl)but-3-ynyl)oxazolo[4,5-b]pyridine 78(A)2-(But-3-ynyl)oxazolo[4,5-b]pyridine

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-aminopyridin-3-ol (449 mg, 4.08 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 7:3 to3:2) to yield 180 mg (1.04 mmol, 26%) of2-(but-3-ynyl)oxazolo[4,5-b]pyridine as a yellow solid.

LCMS (RT): 3.03 min; MS (ES+) gave m/z: 173.0.

78(B) 2-(4-(Pyridin-2-yl)but-3-ynyl)oxazolo[4,5-b]pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-iodopyridine (100 mg, 0.49 mmol) and2-(but-3-ynyl)oxazolo[4,5-b]pyridine (100 mg, 0.58 mmol) at roomtemperature. The crude residue was purified by flash chromatography(DCM/MeOH 99:1 to 98:2) to yield 35 mg (0.14 mmol, 29%) of2-(4-(pyridin-2-yl)but-3-ynyl)oxazolo[4,5-b]pyridine as a brownsemi-solid with a purity of 86%.

LCMS (RT): 2.78 min; MS (ES+) gave m/z: 250.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.10 (t, J=7.5, 2H), 3.35 (t, J=7.5, 2H),7.18-7.21 (m, 1H), 7.26-7.29 (m, 1H), 7.34-7.38 (m, 1H), 7.58-7.63 (m,1H), 7.79 (dd, J=1.5 and 8.0, 1H), 8.52-8.56 (m, 1H), 8.54 (dd, J=1.5and 5.0, 1H).

Example 79 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-5-carbonitrile79(A) 3-Amino-4-hydroxybenzonitrile

The title compound was prepared in accordance with the general method ofExample 62(A), from 4-hydroxy-3-nitrobenzonitrile (1.00 g, 6.09 mmol).817 mg (6.09 mmol, 100%) of 3-amino-4-hydroxybenzonitrile as an orangesolid were obtained and used without purification.

79(B) 2-(But-3-ynyl)benzo[d]oxazole-5-carbonitrile

The title compound was prepared in accordance with the general method ofExample 8(A), from 3-amino-4-hydroxybenzonitrile (547 mg, 4.08 mmol).The crude residue was purified by flash chromatography(cyclohexane/AcOEt 85:15) to yield 212 mg (1.08 mmol, 26%) of2-(but-3-ynyl)benzo[d]oxazole-5-carbonitrile.

LCMS (RT): 3.79 min; MS (ES+) gave m/z: 197.0.

79(C) 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-5-carbonitrile

The title compound was prepared in accordance with the general method ofExample 1, from 2-iodopyridine (89 mg, 0.43 mmol) and2-(but-3-ynyl)benzo[d]oxazole-5-carbonitrile (100 mg, 0.51 mmol) at roomtemperature. The crude residue was purified by flash chromatography(DCM/MeOH 99:1) to yield 45 mg (0.16 mmol, 37%) of2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-5-carbonitrile as a brownsolid.

LCMS (RT): 3.53 min; MS (ES+) gave m/z: 274.0.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (DMSO[D]₆), δ (ppm): 3.05 (t, J=7.5, 2H), 3.34 (t, J=7.5, 2H),7.30-7.35 (m, 1H), 7.37-7.41 (m, 1H), 7.72-7.77 (m, 1H), 7.86 (dd, J=1.5and 8.5, 1H), 7.95 (dd, J=0.5 and 8.5, 1H), 8.34 (d, J=1.5, 1H), 8.49(d, J=4.5, 1H).

Example 807-Chloro-5-fluoro-2-(4-(2-methylthiazol-4-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 4-iodo-2-methylthiazole (200 mg, 0.89 mmol) and2-(but-3-ynyl)-7-chloro-5-fluorobenzo[d]oxazole (199 mg, 0.89 mmol). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt85:15) to yield 157 mg (0.49 mmol, 55%) of7-chloro-5-fluoro-2-(4-(2-methylthiazol-4-yl)but-3-ynyl)benzo[d]oxazoleas a yellow solid.

LCMS (RT): 4.78 min; MS (ES+) gave m/z: 321.0, 323.0.

Rf (cyclohexane/AcOEt 4:1)=0.2.

¹H-NMR (DMSO[D]₆), δ (ppm): 2.60 (s, 3H), 3.00 (t, J=7.5, 2H), 3.30 (t,J=7.5, 2H), 7.55 (dd, J=2.5 and 8.5, 1H), 7.63 (s, 1H), 7.67 (dd, J=2.5and 8.5, 1H).

Example 817-(Trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 81(A)2-Nitro-6-(trifluoromethyl)phenol

The title compound was prepared in accordance with the general method ofExample 77(A) from 2-(trifluoromethyl)phenol (1.98 g, 12.2 mmol).Reaction time: 5 hours. The resulting precipitate was filtered, washedwith water and dried under vacuum to yield2-nitro-6-(trifluoromethyl)phenol (1.10 g, 5.31 mmol, 43%) as a yellowpowder.

81(B) 2-Amino-6-(trifluoromethyl)phenol

The title compound was prepared in accordance with the general method ofExample 62(A), from 2-nitro-6-(trifluoromethyl)phenol (1.10 g, 5.31mmol). Reaction time: 2 days. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 510 mg (2.88 mmol, 54%) of2-amino-6-(trifluoromethyl)phenol.

Rf (DCM/MeOH 99:1)=0.35.

81(C) 2-(But-3-ynyl)-7-(trifluoromethyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-6-(trifluoromethyl)phenol (510 mg, 2.88mmol). Reaction time: 3 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 90 mg (0.38 mmol, 13%)of 2-(but-3-ynyl)-7-(trifluoromethyl)benzo[d]oxazole as a red oil.

81(D) 7-(Trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-iodopyridine (77 mg, 0.38 mmol) and2-(but-3-ynyl)-7-(trifluoromethyl)benzo[d]oxazole (90 mg, 0.38 mmol).The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1 to DCM/MeOH 99:1) to yield 63 mg (0.20 mmol, 53%)of 7-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole asa brown solid.

LCMS (RT): 4.33 min; MS (ES+) gave m/z: 317.0.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.09 (t, J=8.0, 2H), 3.35 (t, J=8.0, 2H),7.17-7.22 (m, 1H), 7.37 (d, J=7.5, 1H), 7.39-7.43 (m, 1H), 7.56 (d,J=8.0, 1H), 7.59-7.63 (m, 1H), 7.88 (d, J=8.0, 1H), 8.50-8.60 (m, 1H).

Example 827-Bromo-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 82(A)2-Bromo-4-fluoro-6-nitrophenol

The title compound was prepared in accordance with the general method ofExample 77(A) from 2-bromo-4-fluorophenol (1.00 g, 5.24 mmol). Reactiontime: 2 hours. The resulting precipitate was filtered, washed with waterand dried under vacuum to yield 2-bromo-4-fluoro-6-nitrophenol (1.20 g,5.08 mmol, 97%) as a yellow powder.

82(B) 2-Amino-6-bromo-4-fluorophenol

The title compound was prepared in accordance with the general method ofExample 62(A), from 2-bromo-4-fluoro-6-nitrophenol (1.20 g, 5.08 mmol).Reaction time: 2 days. The crude residue was purified by flashchromatography (DCM/MeOH 99.5:0.5 to 98:2) to yield 510 mg (2.48 mmol,49%) of 2-amino-6-bromo-4-fluorophenol.

82(C) 7-Bromo-2-(but-3-ynyl)-5-fluorobenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-6-bromo-4-fluorophenol (510 mg, 2.48 mmol).Reaction time: 5 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 223 mg (0.83 mmol, 67%)of 7-bromo-2-(but-3-ynyl)-5-fluorobenzo[d]oxazole.

82(D) 7-Bromo-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (131 mg, 0.83 mmol) and7-bromo-2-(but-3-ynyl)-5-fluoro-benzo[d]oxazole (223 mg, 0.83 mmol). Thecrude residue was purified by flash chromatography (DCM/MeOH 99:1) toyield 130 mg (0.38 mmol, 45%) of7-bromo-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as abrown solid.

LCMS (RT): 4.44 min; MS (ES+) gave m/z: 345.0, 346.9.

Rf (DCM/MeOH 99:1)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 3.08 (t, J=7.9, 2H), 3.33 (t, J=7.9, 2H),7.19-7.23 (m, 1H), 7.24-7.28 (m, 1H), 7.34 (dd, J=2.3 and 8.0, 1H),7.36-7.40 (m, 1H), 7.61-7.65 (m, 1H), 8.54-8.57 (m, 1H).

Example 835-Fluoro-7-phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

To a solution of7-bromo-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole (100 mg,0.29 mmol, Example 82) in dioxane/aqueous saturated solution of NaHCO₃(1:1, 8 mL) were added Pd(PPh₃)₄ (33 mg, 29 μmol) and phenylboronic acid(53.0 mg, 0.43 mmol). The reaction mixture was stirred at 60° C. for 7hours, then AcOEt and brine were added and the organic phase wasdiscarded. The aqueous phase was extracted thrice with AcOEt. Thecombined organic phases were washed with brine, dried over MgSO₄,filtered and concentrated. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 86 mg (0.25 mmol, 87%) of5-fluoro-7-phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as anorange oil.

LCMS (RT): 4.83 min; MS (ES+) gave m/z: 343.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.08 (t, J=7.7, 2H), 3.33 (t, J=7.7, 2H),7.19-7.22 (m, 1H), 7.25-7.29 (m, 1H), 7.32-7.34 (m, 1H), 7.36 (dd, J=2.5and 8.0, 1H), 7.41-7.46 (2H), 7.47-7.52 (2H), 7.58-7.62 (m, 1H),7.81-7.84 (m, 1H), 8.54-8.56 (m, 1H).

Example 84 2-(4-(2-Chloropyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2,4-dichloropyrimidine (200 mg, 1.34 mmol) and2-(but-3-ynyl)benzo[d]oxazole (230 mg, 1.34 mmol, Example 8(A)) at roomtemperature. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 35 mg (0.12 mmol, 9%) of2-(4-(2-chloropyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole as a yellowsolid.

LCMS (RT): 4.11 min; MS (ES+) gave m/z: 284.0.

Example 85 2-Chloro-4-(4-phenylbut-1-ynyl)pyrimidine

The title compound was prepared in accordance with the general method ofExample 1, from 2,4-dichloropyrimidine (250 mg, 1.68 mmol) and1-(but-3-ynyl)benzene (218 mg, 1.68 mmol). The crude residue waspurified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 280 mg(1.15 mmol, 69%) of 2-chloro-4-(4-phenylbut-1-ynyl)pyrimidine as a brownoil.

LCMS (RT): 4.74 min; MS (ES+) gave m/z: 243.1.

Rf (cyclohexane/AcOEt 9:1)=0.3.

Example 86 4-Bromo-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 86(A)3-Methoxy-2-nitrophenylamine

Triethylamine (6.29 mL) and diphenyl azidophosphate (6.66 mL, 30.1 mmol)were added to a suspension of 3-methoxy-2-nitrobenzoic acid (3.00 g,15.2 mmol) in toluene (50 mL). The reaction mixture was stirred underreflux for 2 hours, water (10 mL) was added and it was stirred overnightunder reflux. After evaporation of the solvent, the residue wasdissolved in AcOEt and the resulting solution was filtered throughcelite. The organic phase was washed with saturated solution of NaHCO₃,brine, dried over MgSO₄, filtered and evaporated. The crude residue waspurified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 900 mg(5.35 mmol, 35%) of 3-methoxy-2-nitrophenylamine as a yellow solid.

Rf (DCM/MeOH 4:1)=0.1.

86(B) 1-Bromo-3-methoxy-2-nitrobenzene

3-Methoxy-2-nitro-phenylamine (360 mg, 2.14 mmol) was dissolved in HBr(48%, 4.8 mL) at 0° C. A solution of sodium nitrite (0.16 g, 2.40 mmol)in water (360 μL) was added dropwise to the stirred solution over onehour period while the temperature was maintained at 0° C. Then a cold(0° C.) freshly prepared solution of CuBr₂ (from CuSO₄.5H₂O (1.0 g) andHBr (48%, 1.0 mL) mixed 30 min. at room temperature to give a darkpurple solution) was added at 0° C. to the reaction mixture. Theresulting solution was stirred at 0° C. for 3 hours and at roomtemperature for 2 days. The reaction mixture was poured onto ice andneutralized carefully with a saturated solution of NaHCO₃. The aqueousphase was extracted with AcOEt. The resulting organic phase was washedwith brine, dried over MgSO₄, filtered and evaporated to yield 482 mg(2.08 mmol, 97%) of 1-bromo-3-methoxy-2-nitrobenzene as an orange solid.

86(C) 2-Bromo-6-methoxyphenylamine

The title compound was prepared in accordance with the general method ofExample 62(A), from 1-bromo-3-methoxy-2-nitrobenzene (482 mg, 2.08 mmol)to yield 375 mg (1.86 mmol, 89%) of 2-bromo-6-methoxyphenylamine.

86(D) 2-Amino-3-bromophenol

BBr₃ (3.71 mL, 3.71 mmol, 1 M in DCM) was added at 0° C. to a solutionof 2-bromo-6-methoxyphenylamine (375 mg, 1.86 mmol) in DCM (10 mL). Thereaction mixture was stirred under reflux for 2 hours and was quenchedby the addition of MeOH followed by a saturated solution of NaHCO₃. Theaqueous phase was extracted with AcOEt. The resulting organic layer waswashed with brine dried over MgSO₄, filtered and evaporated. The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 7:3 toDCM) to yield 204 mg (1.08 mmol, 58%) of 2-amino-3-bromophenol as asolid.

86(E) 4-Bromo-2-(but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-3-bromophenol (200 mg, 1.06 mmol). Reactiontime: 4 days. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 100 mg (0.40 mmol, 38%) of4-bromo-2-(but-3-ynyl)benzo[d]oxazole.

86(F) 4-Bromo-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (63 mg, 0.40 mmol) and4-bromo-2-(but-3-ynyl)-benzo[d]oxazole (100 mg, 0.40 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1) to yield 60mg (0.18 mmol, 46%) of4-bromo-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solidwith a purity of 85%.

LCMS (RT): 4.09 min; MS (ES+) gave m/z: 327.0, 329.0.

Rf (DCM/MeOH 99:1)=0.1.

Example 87 4-Phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 83, from 4-bromo-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole(60 mg, 0.18 mmol, Example 86). The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 8 mg (25 mmol, 10%) of4-phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oilwith a purity of 80%.

LCMS (RT): 4.89 min; MS (ES+) gave m/z: 325.2.

Rf (DCM/MeOH 99:1)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 3.08 (t, J=7.3, 2H), 3.34 (t, J=7.3, 2H),7.19-7.23 (m, 1H), 7.35-7.42 (3H), 7.47-7.53 (4H), 7.58-7.63 (m, 1H),7.93-7.98 (2H), 8.53-8.57 (m, 1H).

Example 88 4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 88(A)1-Chloro-3-methoxy-2-nitrobenzene

A solution of sodium nitrite (180 mg, 2.60 mmol) in water (0.5 mL) wasadded dropwise to a solution of 3-methoxy-2-nitro-phenylamine (400 mg,2.38 mmol, Example 86(A)) in HCl (37%, 3.9 mL) at 0° C. over one hourperiod. Then the reaction mixture was added to a cold (0° C.) solutionof CuCl₂ (640 mg, 4.76 mmol) in HCl (6 N, 3.5 mL). The resulting greensolution was stirred at room temperature for 2 days. Then, the reactionmixture was poured onto ice and neutralized carefully with a saturatedsolution of NaHCO₃. The aqueous phase was extracted with AcOEt. Theresulting organic phase was washed with brine, dried over MgSO₄,filtered and evaporated to yield 293 mg (1.56 mmol, 66%) of1-chloro-3-methoxy-2-nitrobenzene as a brown oil.

88(B) 2-Chloro-6-methoxyphenylamine

The title compound was prepared in accordance with the general method ofExample 62(A), from 1-chloro-3-methoxy-2-nitrobenzene (293 mg, 1.56mmol) to yield 214 mg (1.36 mmol, 87%) of 2-chloro-6-methoxyphenylamine.

Rf (DCM/MeOH 99:1)=0.3.

88(C) 2-Amino-3-chlorophenol

The title compound was prepared in accordance with the general method ofExample 86(D), from 2-chloro-6-methoxyphenylamine (397 mg, 2.52 mmol).The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1 to DCM) to yield 45 mg (0.31 mmol, 12%) of2-amino-3-chlorophenol as a red oil.

88(D) 2-(But-3-ynyl)-4-chlorobenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-3-chlorophenol (50.0 mg, 0.35 mmol). Reactiontime: 4 days. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 20 mg (97 mmol, 28%) of2-(but-3-ynyl)-4-chlorobenzo[d]oxazole.

88(E) 4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (15 mg, 97 μmol) and2-(but-3-ynyl)-4-chlorobenzo[d]oxazole (20 mg, 97 μmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 4:1) toyield 3 mg (11 μmol, 11%) of4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid.

LCMS (RT): 3.99 min; MS (ES+) gave m/z: 283.0, 285.0.

Rf (cyclohexane/AcOEt 4:1)=0.05.

Example 89 5,7-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole89(A) 2-(But-3-ynyl)-5,7-difluorobenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-4,6-difluorophenol (500 mg, 3.45 mmol).Reaction time: 3 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 309 mg (1.49 mmol, 43%)of 2-(but-3-ynyl)-5,7-difluorobenzo[d]oxazole.

89(B) 5,7-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (236 mg, 1.49 mmol) and2-(but-3-ynyl)-5,7-difluoro benzo[d]oxazole (309 mg, 1.49 mmol). Thecrude residue was purified by flash chromatography (DCM/MeOH 99:1) toyield 86 mg (0.3 mmol, 20%) of5,7-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brownsolid (M.P.: 93.5-94° C.).

LCMS (RT): 4.09 min; MS (ES+) gave m/z: 285.1.

Rf (DCM/MeOH 99:1)=0.05.

¹H-NMR (CDCl₃), δ (ppm): 3.07 (t, J=8.0, 2H), 3.31 (t, J=8.0, 2H),6.85-6.90 (m, 1H), 7.18-7.22 (2H), 7.35-7.38 (m, 1H), 7.59-7.64 (m, 1H),8.53-8.56 (m, 1H).

Example 90 4-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 90(A)6-Bromo-3-fluoro-2-nitrophenol

The title compound was prepared in accordance with the general method ofExample 77(A) from 2-bromo-5-fluorophenol (1.16 mL, 10.5 mmol). Reactiontime: 6 hours. As there was no preciptate, the reaction mixture waspoured onto ice, neutralized with NaOH and extracted with DCM. Theorganic phase was washed with brine, dried over MgSO₄, filtered andevaporated to yield 6-bromo-3-fluoro-2-nitrophenol (2.30 g, 9.75 mmol,93%) mixed with 2-bromo-5-fluoro-4-nitrophenol.

90(B) 2-Amino-3-fluorophenol

The title compound was prepared in accordance with the general method ofExample 62(A), from crude 6-bromo-3-fluoro-2-nitrophenol (2.30 g, 9.75mmol). Reaction time: 2 days. The crude residue was purified by flashchromatography (DCM/MeOH 99.5:0.5) to yield 56.0 mg (0.44 mmol, 5%) of2-amino-3-fluorophenol.

90(C) 2-(But-3-ynyl)-4-fluorobenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-3-fluorophenol (56 mg, 0.44 mmol). Reactiontime: 2 days. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 35 mg (0.18 mmol, 42%) of2-(but-3-ynyl)-4-fluorobenzo[d]oxazole.

90(D) 4-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (29.2 mg, 0.18 mmol) and2-(but-3-ynyl)-4-fluorobenzo[d]oxazole (35 mg, 0.18 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) toyield 24 mg (90 mmol, 49%) of4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orangesolid (M.P.=89-89.5° C.).

LCMS (RT): 3.81 min; MS (ES+) gave m/z: 267.0.

Rf (DCM/MeOH 98:2)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 3.06 (t, J=8.0, 2H), 3.29 (t, J=8.0, 2H),7.04-7.09 (m, 1H), 7.18-7.21 (m, 1H), 7.23 (dd, J=2.5 and 8.0, 1H), 7.36(d, J=8.0, 1H), 7.59-7.63 (2H), 8.52-8.56 (m, 1H).

Example 91 7-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 91(A)2-Amino-6-methylphenol

The title compound was prepared in accordance with the general method ofExample 62(A), from 2-methyl-6-nitrophenol (170 mg, 1.11 mmol). Reactiontime: 1 day. The crude residue was purified by flash chromatography(DCM/MeOH 99:1) to yield 41 mg (0.33 mmol, 30%) of2-amino-6-methylphenol.

Rf (DCM/MeOH 99:1)=0.1.

91(B) 2-(But-3-ynyl)-7-methylbenzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-6-methylphenol (41 mg, 0.33 mmol). Reactiontime: 2 days. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 30 mg (0.16 mmol, 49%) of2-(but-3-ynyl)-7-methylbenzo[d]oxazole.

91(C) 7-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (26 mg, 0.16 mmol) and2-(but-3-ynyl)-7-methyl benzo[d]oxazole (30 mg, 0.16 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 98.5:1.5) toyield 23 mg (87 μmol, 54%) of7-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil.

LCMS (RT): 3.99 min; MS (ES+) gave m/z: 263.1.

Rf (DCM/MeOH 99:1)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 2.51 (s, 3H), 3.07 (t, J=8.0, 2H), 3.30 (t,J=8.0, 2H), 7.11 (d, J=7.5, 1H), 7.17-7.24 (2H), 7.36 (d, J=7.5, 1H),7.51 (d, J=8.0, 1H), 7.59-7.63 (m, 1H), 8.54 (d, J=4.0, 1H).

Example 92 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-7-carbonitrile92(A) 2-(But-3-ynyl)benzo[d]oxazole-7-carbonitrile

The title compound was prepared in accordance with the general method ofExample 8(A), from 3-amino-2-hydroxybenzonitrile (500 mg, 3.73 mmol).Reaction time: 3 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 535 mg (2.73 mmol, 73%)of 2-(but-3-ynyl)benzo[d]oxazole-7-carbonitrile.

92(B) 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-7-carbonitrile

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (161 mg, 1.02 mmol) and2-(but-3-ynyl)benzo[d]oxazole-7-carbonitrile (200 mg, 1.02 mmol). Thecrude residue was purified by flash chromatography (DCM/MeOH 99:1) toyield 48 mg (0.18 mmol, 17%) of2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-7-carbonitrile as a yellowsolid (M.P.=126-126.5° C.).

LCMS (RT): 3.61 min; MS (ES+) gave m/z: 274.1.

¹H-NMR (CDCl₃), δ (ppm): 3.10 (t, J=7.5, 2H), 3.36 (t, J=7.5, 2H),7.18-7.22 (m, 1H), 7.39 (d, J=7.5, 1H), 7.39-7.44 (m, 1H), 7.59-7.64(2H), 7.93 (dd, J=1.0 and 8.0, 1H), 8.54 (d, J=4.5, 1H).

Example 937-Chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 93(A)6-Chloro-3-fluoro-2-nitrophenol

The title compound was prepared in accordance with the general method ofExample 77(A) from 2-chloro-5-fluoro-phenol (2.00 g, 13.6 mmol).Reaction time: 5 hours. The reaction mixture was poured onto ice andextracted with AcOEt. The organic phase was washed with saturatedsolution of NaHCO₃, water, dried over MgSO₄, filtered and evaporated toyield 6-chloro-3-fluoro-2-nitrophenol (2.56 g, 13.4 mmol).

93(B) 2-Amino-6-chloro-3-fluorophenol

The title compound was prepared in accordance with the general method ofExample 62(A), from 6-chloro-3-fluoro-2-nitrophenol (2.56 g, 13.4 mmol).Reaction time: 1 day. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 1.01 g (6.26 mmol, 47%) of2-amino-6-chloro-3-fluorophenol.

93(C) 2-(But-3-ynyl)-7-chloro-4-fluoro-benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-6-chloro-3-fluorophenol (1.01 g, 6.26 mmol).Reaction time: 3 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 176 mg (0.79 mmol, 13%)of 2-(but-3-ynyl)-7-chloro-4-fluoro-benzo[d]oxazole.

93(D) 7-Chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (124 mg, 0.79 mmol) and2-(but-3-ynyl)-7-chloro-4-fluoro-benzo[d]oxazole (176 mg, 0.79 mmol).The crude residue was purified by flash chromatography (DCM/MeOH 99:1)to yield 30 mg (99 mmol, 13%) of7-chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as abrown solid (M.P.=102-103° C.).

LCMS (RT): 4.31 min; MS (ES+) gave m/z: 301.0, 303.0.

¹H-NMR (CDCl₃), δ (ppm): 3.09 (t, J=8.0, 2H), 3.34 (t, J=8.0, 2H),6.99-7.04 (m, 1H), 7.18-7.22 (m, 1H), 7.24-7.29 (m, 1H), 7.36-7.40 (m,1H), 7.60-7.64 (m, 1H), 8.53-8.55 (m, 1H).

Example 94 7-Methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 94(A)3-Aminobenzene-1,2-diol

The title compound was prepared in accordance with the general method ofExample 62(A), from 3-nitrobenzene-1,2-diol (1.00 g, 6.45 mmol). 392 mg(3.13 mmol, 49%) of 3-aminobenzene-1,2-diol as a brown solid wereobtained and used without purification.

94(B) 2-(But-3-ynyl)benzo[d]oxazol-7-ol

The title compound was prepared in accordance with the general method ofExample 8(A), from 3-aminobenzene-1,2-diol (392 mg, 3.13 mmol). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt9:1 to 7:3) to yield 130 mg (0.69 mmol, 22%) of2-(but-3-ynyl)benzo[d]oxazol-7-ol.

94(C) 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-7-ol

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (110 mg, 0.69 mol) and2-(but-3-ynyl)benzo[d]oxazol-7-ol (130 mg, 0.69 mmol). The crude residuewas purified by flash chromatography (DCM/MeOH 98:2) to yield 10 mg (38μmol, 5%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-7-ol.

Rf (DCM/MeOH 98:2)=0.1.

94(D) 7-Methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 72, from 2-(4-pyridin-2-yl-but-3-ynyl)-benzo[d]oxazol-7-ol (10mg, 38 μmol). The crude residue was purified by flash chromatography(DCM/MeOH 99:1) to yield 3.7 mg (13 μmol, 35%) of7-methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oilwith a purity of 82%.

LCMS (RT): 3.56 min; MS (ES+) gave m/z: 279.2.

Rf (DCM/MeOH 99:1)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 3.08 (t, J=8.1, 2H), 3.31 (t, J=8.1, 2H), 4.03(s, 3H), 6.86 (d, J=8.1, 1H), 7.18-7.22 (m, 1H), 7.22-7.26 (m, 1H), 7.32(dd, J=0.8 and 8.0, 1H), 7.39 (d, J=8.0, 1H), 7.59-7.64 (m, 1H),8.53-8.57 (m, 1H).

Example 95 7-Isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole95(A) 2-Isopropyl-6-nitrophenol

The title compound was prepared in accordance with the general method ofExample 77(A) from 2-isopropylphenol (2.00 g, 14.7 mmol). Reaction time:6 hours. The reaction mixture was poured onto ice and extracted withAcOEt. The organic phase was washed with brine, dried over MgSO₄,filtered and evaporated to yield 2-isopropyl-6-nitrophenol (2.50 g, 13.8mmol, 94%).

95(B) 2-Amino-6-isopropylphenol

The title compound was prepared in accordance with the general method ofExample 62(A), from 2-isopropyl-6-nitrophenol (2.50 g, 13.8 mmol). Thecrude residue was purified by flash chromatography (DCM/MeOH 99:1) toyield 974 mg (6.44 mmol, 47%) of 2-amino-6-isopropylphenol.

95(C) 2-But-3-ynyl-7-isopropyl-benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-6-isopropylphenol (974 mg, 6.44 mmol).Reaction time: 2 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 55 mg (0.26 mmol, 4%) of2-(but-3-ynyl)-7-isopropyl-benzo[d]oxazole.

95(D) 7-Isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (41 mg, 0.26 mmol) and2-(but-3-ynyl)-7-isopropyl-benzo[d]oxazole (55 mg, 0.26 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1) to yield4.2 mg (14 mmol, 6%) of7-isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a red oil.

LCMS (RT): 4.56 min; MS (ES+) gave m/z: 291.2.

Rf (DCM/MeOH 97.5:2.5)=0.3.

¹H-NMR (CDCl₃), δ (ppm): 1.37 (d, J=7.0, 6H), 3.07 (t, J=8.0, 2H), 3.31(t, J=8.0, 2H), 3.31-3.37 (m, 1H), 7.15 (dd, J=1.0 and 7.5, 1H),7.17-7.21 (m, 1H), 7.22-7.26 (m, 1H), 7.34-7.37 (m, 1H), 7.52 (dd, J=1.0and 8.0, 1H), 7.58-7.62 (m, 1H), 8.53-8.56 (m, 1H).

Example 96 4,7-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole96(A) 3,6-Difluoro-2-nitrophenol

The title compound was prepared in accordance with the general method ofExample 77(A) from 2,5-difluorophenol (1.00 g, 7.69 mmol). Reactiontime: 6 hours. The reaction mixture was poured onto ice and extractedwith AcOEt. The organic phase was washed with brine, dried over MgSO₄,filtered and evaporated to yield 3,6-difluoro-2-nitrophenol (1.28 g,7.30 mmol).

96(B) 2-Amino-3,6-difluorophenol

The title compound was prepared in accordance with the general method ofExample 62(A), from 3,6-difluoro-2-nitrophenol (1.28 g, 7.30 mmol).Reaction time: 4 days. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 836 mg (5.76 mmol, 79%) of2-amino-3,6-difluorophenol.

96(C) 2-(But-3-ynyl)-4,7-difluoro-benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-3,6-difluorophenol (836 mg, 5.76 mmol). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt4:1) to yield 90 mg (0.43 mmol, 7%) of2-(but-3-ynyl)-4,7-difluoro-benzo[d]oxazole.

96(D) 4,7-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (69 mg, 0.43 mmol) and2-(but-3-ynyl)-4,7-difluoro-benzo[d]oxazole (90 mg, 0.43 mmol). Thecrude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5)to yield 17 mg (61 μmol, 14%) of4,7-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orangesolid.

LCMS (RT): 3.99 min; MS (ES+) gave m/z: 285.1.

Rf (DCM/MeOH 98.5:1.5)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 3.09 (t, J=7.5, 2H), 3.33 (t, J=7.5, 2H),6.94-7.05 (2H), 7.18-7.22 (m, 1H), 7.36-7.39 (m, 1H), 7.59-7.64 (m, 1H),8.53-8.56 (m, 1H).

Example 977-Fluoro-4-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole97(A) 6-Fluoro-2-nitro-3-(trifluoromethyl)phenol

The title compound was prepared in accordance with the general method ofExample 77(A) from 2-fluoro-5-(trifluoromethyl)phenol (1.00 g, 5.55mmol). Reaction time: 6 hours. The reaction mixture was poured onto iceand extracted with AcOEt. The organic phase was washed with brine, driedover MgSO₄, filtered and evaporated to yield6-fluoro-2-nitro-3-(trifluoromethyl)phenol (1.21 g, 5.39 mmol).

97(B) 2-Amino-6-fluoro-3-(trifluoromethyl)phenol

The title compound was prepared in accordance with the general method ofExample 62(A), from 6-fluoro-2-nitro-3-(trifluoromethyl)phenol (1.21 g,5.38 mmol). Reaction time: 1 day. The crude residue was purified byflash chromatography (DCM/MeOH 99:1) to yield 320 mg (1.64 mmol, 30%) of2-amino-6-fluoro-3-(trifluoromethyl)phenol.

97(C) 2-(But-3-ynyl)-7-fluoro-4-(trifluoromethyl)-benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-6-fluoro-3-(trifluoromethyl)phenol (320 mg,1.64 mmol). Reaction time: 2 days. The crude residue was purified byflash chromatography (cyclohexane/AcOEt 4:1) to yield 80 mg (0.31 mmol,19%) of 2-(but-3-ynyl)-7-fluoro-4-(trifluoromethyl)-benzo[d]oxazole.

97(D)7-Fluoro-4-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (49 mg, 0.31 mmol) and2-(but-3-ynyl)-7-fluoro-4-(trifluoromethyl)-benzo[d]oxazole (80 mg, 0.31mmol). The crude residue was purified by flash chromatography (DCM/MeOH98.5:1.5) to yield 15 mg (44 mmol, 14%) of7-fluoro-4-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazoleas an orange solid.

LCMS (RT): 4.44 min; MS (ES+) gave m/z: 335.1.

Rf (DCM/MeOH 98.5:1.5)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.09 (t, J=8.0, 2H), 3.39 (t, J=8.0, 2H),7.13-7.18 (m, 1H), 7.19-7.22 (m, 1H), 7.35-7.38 (m, 1H), 7.55-7.59 (m,1H), 7.60-7.64 (m, 1H), 8.52-8.56 (m, 1H).

Example 98 2-(4-(Pyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole 98(A)4-Chloropyrimidine

Pyrimidin-4-ol (200 mg, 2.08 mmol) was dissolved in phosphorous chloride(2 mL), the reaction mixtue was stirred for 1 hour at 100° C. and pouredonto ice. The aqueous phase was neutralized with NaOH and extracted withAcOEt. The organic phase was washed with brine, dried over MgSO₄,filtered and evaporated to yield 4-chloropyrimidine (85 mg, 0.74 mmol,36%) as an orange oil.

98(B) 2-(4-(Pyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole

The title compound was prepared in accordance with the general method ofExample 1, from 4-chloropyrimidine (85 mg, 0.74 mmol) and2-(but-3-ynyl)benzo[d]oxazole (127 mg, 0.74 mmol). The crude residue waspurified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 32 mg(128 μmol, 17%) of 2-(4-(pyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole as awhite solid.

Rf (cyclohexane/AcOEt 1:1)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.12 (t, J=7.9, 2H), 3.32 (t, J=7.9, 2H), 7.31(dd, J=1.1 and 5.1, 1H), 7.33-7.36 (2H), 7.50-7.54 (m, 1H), 7.69-7.72(m, 1H), 8.67 (d, J=5.1 1H), 9.15 (d, J=1.1, 1H).

Example 99 N-(3-Chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide99(A) Pent-4-ynoic acid (3-chloro-phenyl)-methyl-amide

Oxayl chloride (89 μL, 1.02 mmol) was added to a solution ofpent-4-ynoic acid (50 mg, 0.51 mmol) in DCM (3 mL). The reaction mixturewas stirred at 50° C. for 1 hour, was cooled to 0° C. and was addeddropwise to a solution of (3-chloro-phenyl)-methyl-amine (62 μL, 0.51mmol). The reaction mixture was stirred for 2 hours at room temperature.After evaporation of the solvent, the crude residue was purified byflash chromatography (DCM/MeOH 99:1) to yield 100 mg (0.45 mmol, 88%) ofpent-4-ynoic acid (3-chloro-phenyl)-methyl-amide.

LCMS (RT): 3.94 min; MS (ES+) gave m/z: 222.0.

99(B) N-(3-Chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (80 mg, 0.51 mmol) and pent-4-ynoic acid(3-chloro-phenyl)-methyl-amide (113 mg, 0.51 mmol). The crude residuewas purified by C₁₈ flash chromatography to yield 51 mg (0.17 mmol, 33%)of N-(3-chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide as a brownliquid.

LCMS (RT): 3.73 min; MS (ES+) gave m/z: 299.1, 301.1.

¹H-NMR (CDCl₃), δ (ppm): 2.39-2.50 (m, 2H), 2.76 (t, J=7.5, 2H), 3.28(s, 3H), 7.11-7.15 (m, 1H), 7.16-7.20 (m, 1H), 7.24-7.27 (m, 1H),7.32-7.39 (m, 1H), 7.45-7.50 (m, 1H), 7.58-7.63 (m, 1H), 7.65-7.71 (m,1H), 8.52 (d, J=4.8, 1H).

Example 1007-Chloro-4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole 100(A)2-Amino-6-chloro-3-methyl-benzenethiol

To a solution of NaOH (10N, 8.0 mL) was added7-chloro-4-methyl-benzothiazol-2-ylamine (530 mg, 2.67 mmol) andethylene glycol (10 mL) then the reaction mixture was stirred at 150° C.for 1 day. After being cooled down, the reaction mixture was filtered.The filtrate was extracted with DCM. The aqueous phase was acidifiedwith HCl 1N and extracted with DCM. Then, the combined organic phaseswere washed with brine, dried over MgSO₄, filtered and evaporated toyield 2-amino-6-chloro-3-methyl-benzenethiol (252 mg, 1.45 mmol, 54%) asa yellow oil.

100(B) 2-But-3-ynyl-7-chloro-4-methyl-benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-6-chloro-3-methyl-benzenethiol (252 mg, 1.45mmol). Reaction time: 2 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 30 mg (0.13 mmol, 9%) of2-but-3-ynyl-7-chloro-4-methyl-benzo[d]thiazole as an orange oil.

100(C) 7-Chloro-4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (20 mg, 0.13 mmol) and2-but-3-ynyl-7-chloro-4-methyl-benzo[d]thiazole (30 mg, 0.13 mmol). Thecrude residue was purified by flash chromatography (DCM/MeOH 99:1 to98:2) to yield 2.9 mg (9.3 mmol, 7%) of7-chloro-4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as abrown oil.

LCMS (RT): 5.04 min; MS (ES+) gave m/z: 313.1, 315.0.

Rf (DCM/MeOH 97:3)=0.3.

¹H-NMR (CDCl₃), δ (ppm): 2.70 (s, 3H), 3.05 (t, J=7.5, 2H), 3.46 (t,J=7.5, 2H), 7.18-7.22 (2H), 7.24-7.27 (m, 1H), 7.37-7.40 (m, 1H),7.60-7.64 (m, 1H), 8.54-8.57 (m, 1H).

Example 101 4-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole101(A) 2-Amino-3-fluoro-benzenethiol

The title compound was prepared in accordance with the general method ofExample 100(A), from 4-fluoro-benzothiazol-2-ylamine (603 mg, 3.58 mmol)to yield 2-amino-3-fluoro-benzenethiol (513 mg, 3.58 mmol) as a yellowsolid.

101(B) 2-But-3-ynyl-4-fluoro-benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-3-fluoro-benzenethiol (513 mg, 3.58 mmol).Reaction time: 2 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 378 mg (1.84 mmol, 51%)of 2-but-3-ynyl-4-fluoro-benzo[d]thiazole as an orange oil.

101(C) 4-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (291 mg, 1.84 mmol) and2-but-3-ynyl-4-fluoro-benzo[d]thiazole (378 mg, 1.84 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1) to yield 10mg (37 μmol, 2%) of4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a yellowsolid.

LCMS (RT): 3.89 min; MS (ES+) gave m/z: 283.0.

Rf (DCM/MeOH 98:2)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 3.05 (t, J=7.5, 2H), 3.48 (t, J=7.5, 2H),7.15-7.22 (2H), 7.30-7.35 (m, 1H), 7.38 (d, J=8.0, 1H), 7.60-7.65 (2H),8.55 (d, J=5.0, 1H).

Example 102 4,7-Dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole102(A) 2-Amino-3,6-dimethyl-benzenethiol

The title compound was prepared in accordance with the general method ofExample 100(A), from 4,7-dimethyl-benzothiazol-2-ylamine (580 mg, 3.25mmol) to yield 2-amino-3,6-dimethyl-benzenethiol (200 mg, 1.30 mmol,40%) as a yellow oil.

102(B) 2-But-3-ynyl-4,7-dimethyl-benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-3,6-dimethyl-benzenethiol (200 mg, 1.30mmol). Reaction time: 2 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 63 mg (0.29 mmol, 22%)of 2-but-3-ynyl-4,7-dimethyl-benzo[d]thiazole.

102(C) 4,7-Dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (46 mg, 0.29 mmol) and2-but-3-ynyl-4,7-dimethyl-benzo[d]thiazole (63 mg, 0.29 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) toyield 15 mg (52 mmol, 18%) of4,7-dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a yellowsolid.

LCMS (RT): 4.73 min; MS (ES+) gave m/z: 293.1.

Rf (DCM/MeOH 98:2)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 2.50 (s, 3H), 2.70 (s, 3H), 3.04 (t, J=7.5,2H), 3.47 (t, J=7.5, 2H), 7.06 (d, J=7.5, 1H), 7.18 (d, J=7.5, 1H),7.19-7.21 (m, 1H), 7.36-7.39 (m, 1H), 7.60-7.64 (m, 1H), 8.54-8.57 (m,1H).

Example 103 4-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole103(A) 2-Amino-3-methyl-benzenethiol

The title compound was prepared in accordance with the general method ofExample 100(A), from 4-methyl-benzothiazol-2-ylamine (1.00 g, 6.09 mmol)to yield 2-amino-3-methyl-benzenethiol (463 mg, 3.33 mmol, 55%).

103(B) 2-But-3-ynyl-4-methyl-benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-3-methyl-benzenethiol (463 mg, 3.33 mmol).Reaction time: 2 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 246 mg (1.22 mmol, 37%)of 2-but-3-ynyl-4-methyl-benzo[d]thiazole.

103(C) 4-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (193 mg, 1.22 mmol) and2-but-3-ynyl-4-methyl-benzo[d]thiazole (246 mg, 1.22 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) toyield 86 mg (0.31 mmol, 25%) of4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil.

LCMS (RT): 4.33 min; MS (ES+) gave m/z: 279.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 2.74 (s, 3H), 3.04 (t, J=7.5, 2H), 3.46 (t,J=7.5, 2H), 7.18-7.22 (m, 1H), 7.24-7.26 (2H), 7.36-7.39 (m, 1H),7.59-7.64 (m, 1H), 7.65-7.70 (m, 1H), 8.54-8.57 (m, 1H).

Example 104 5-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole104(A) 2-Amino-4-fluoro-benzenethiol

The title compound was prepared in accordance with the general method ofExample 100(A), from 5-fluoro-benzothiazol-2-ylamine (520 mg, 3.09 mmol)to yield 2-amino-4-fluoro-benzenethiol (443 mg, 3.09 mmol) as a yellowsolid.

104(B) 2-But-3-ynyl-5-fluoro-benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-4-fluoro-benzenethiol (443 mg, 3.09 mmol).Reaction time: 2 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 286 mg (1.39 mmol, 45%)of 2-but-3-ynyl-5-fluoro-benzo[d]thiazole.

104(C) 5-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (220 mg, 1.39 mmol) and2-but-3-ynyl-5-fluoro-benzo[d]thiazole (286 mg, 1.39 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) toyield 38 mg (0.13 mmol, 10%) of5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as an orangesolid.

LCMS (RT): 3.98 min; MS (ES+) gave m/z: 283.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.03 (t, J=7.5, 2H), 3.43 (t, J=7.5, 2H),7.17-7.22 (2H), 7.36-7.38 (m, 1H), 7.53 (dd, J=2.5 and 8.5, 1H),7.59-7.64 (m, 1H), 7.92 (dd, J=4.5 and 8.5, 1H), 8.54-8.56 (m, 1H).

Example 105 4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole105(A) 2-Amino-3-chloro-benzenethiol

The title compound was prepared in accordance with the general method ofExample 100(A), from 4-chloro-benzothiazol-2-ylamine (584 mg, 3.16 mmol)to yield 2-amino-3-chloro-benzenethiol (364 mg, 2.28 mmol, 74%) as ayellow solid.

105(B) 2-But-3-ynyl-4-chloro-benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-3-chloro-benzenethiol (364 mg, 2.28 mmol).Reaction time: 2 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 233 mg (1.05 mmol, 46%)of 2-but-3-ynyl-4-chloro-benzo[d]thiazole.

105(C) 4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (166 mg, 1.05 mmol) and2-but-3-ynyl-4-chloro-benzo[d]thiazole (233 mg, 1.05 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) toyield 46 mg (0.15 mmol, 14%) of4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil.

LCMS (RT): 4.18 min; MS (ES+) gave m/z: 299.1, 301.1.

Rf (DCM/MeOH 98:2)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 3.04 (t, J=7.5, 2H), 3.50 (t, J=7.5, 2H),7.18-7.22 (m, 1H), 7.27-7.32 (m, 1H), 7.39 (d, J=7.5, 1H), 7.49 (dd,J=1.0 and 8.0, 1H), 7.60-7.65 (m, 1H), 7.75 (dd, J=1.0 and 8.0, 1 H),8.53-8.59 (m, 1H).

Example 106 N-(2-Chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide106(A) Pent-4-ynoic acid (2-chloro-phenyl)-methyl-amide

The title compound was prepared in accordance with the general method ofExample 99(A), from (2-chloro-phenyl)-methyl-amine (0.19 mL, 1.53 mmol).The crude residue was purified by flash chromatography (DCM/MeOH 99:1)to yield 220 mg (1.00 mmol, 65%) of pent-4-ynoic acid(2-chloro-phenyl)-methyl-amide.

LCMS (RT): 3.91 min; MS (ES+) gave m/z: 222.0.

106(B) N-(2-Chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (157 mg, 1.00 mmol) and pent-4-ynoicacid (2-chloro-phenyl)-methyl-amide (220 mg, 1.00 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 98:2) to yield 20mg (66 mmol, 7%) ofN-(2-chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide as a brownliquid.

LCMS (RT): 3.61 min; MS (ES+) gave m/z: 299.1.

¹H-NMR (CDCl₃), δ (ppm): 2.26-2.40 (m, 2H), 2.68-2.81 (m, 2H), 3.22 (s,3H), 7.14-7.19 (m, 1H), 7.28-7.40 (4H), 7.49-7.53 (m, 1H), 7.55-7.61 (m,1H), 8.49 (d, J=6.0, 1H).

Example 107 1-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole107(A) 2-Chloromethyl-1-methyl-1H-benzoimidazole

A solution of (1-methyl-1H-benzoimidazol-2-yl)-methanol (500 mg, 3.08mmol) and SOCl₂ (1.1 mL) in DCM (2 mL) was stirred at room temperaturefor 3 hours. After evaporation of the solvents,2-chloromethyl-1-methyl-1H-benzoimidazole (556 mg, 3.08 mmol) wasobtained and was used without any purification.

107(B) 1-Methyl-2-(4-trimethylsilanyl-but-3-ynyl)-1H-benzoimidazole

n-BuLi (1.35 mL, 3.39 mmol, 2.5 M) was added to a solution oftrimethyl-prop-1-ynyl-silane (0.55 mL, 3.69 mmol) in THF (1 mL) at −78°C. After 2 hours, a solution of2-chloromethyl-1-methyl-1H-benzoimidazole (556 mg, 3.08 mmol) in THF (8mL) was added to the reaction mixture at −78° C. then the reactionmixture was stirred for 30 min. at −78° C. and 1 hour at roomtemperature and was quenched with water. The aqueous phase was extractedwith DCM. The organic phase was washed with water, dried over MgSO₄,filtered and evaporated to yield1-methyl-2-(4-trimethylsilanyl-but-3-ynyl)-1H-benzoimidazole (178 mg,0.69 mmol, 23%).

LCMS (RT): 3.13 min; MS (ES+) gave m/z: 257.2.

107(C) 2-But-3-ynyl-1-methyl-1H-benzoimidazole

TBAF (0.24 mL, 0.83 mmol) was added to a solution of1-methyl-2-(4-trimethylsilanyl-but-3-ynyl)-1H-benzoimidazole (178 mg,0.69 mmol) in THF (2.5 mL) and the reaction mixture was stirred for 2hours at room temperature. After the addition of water, the solvent wasevaporated and the aqueous phase was extracted with DCM. The organicphase was washed with brine, dried over MgSO₄, filtered and evaporated.The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 90 mg (0.49 mmol, 70%) of2-but-3-ynyl-1-methyl-1H-benzoimidazole as a brown solid.

LCMS (RT): 1.99 min; MS (ES+) gave m/z: 185.2.

107(D) 1-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-iodo-pyridine (100 mg, 0.49 mmol) and2-but-3-ynyl-1-methyl-1H-benzoimidazole (90 mg, 0.49 mmol). Reactiontime: 18 hours. The crude residue was purified by flash chromatography(DCM/MeOH 98:2) to yield 39 mg (0.15 mmol, 31%) of1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as a brownsolid.

LCMS (RT): 2.33 min; MS (ES+) gave m/z: 262.1.

¹H-NMR (CDCl₃), δ (ppm): 3.10 (t, J=7.2, 2H), 3.27 (t, J=7.2, 2H), 3.81(s, 3H), 7.19-7.23 (m, 1H), 7.24-7.30 (2H), 7.31-7.34 (m, 1H), 7.36 (d,J=7.8, 1H), 7.59-7.65 (m, 1H), 7.72-7.76 (m, 1H), 8.56 (d, J=4.3, 1H).

Example 108 2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-indazole 108(A)2-(4-Trimethylsilanyl-but-3-ynyl)-2H-indazole and1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole

A suspension of (4-bromo-but-1-ynyl)-trimethyl-silane (374 mg, 1.83mmol), indazole (200 mg, 1.69 mmol) and K₂CO₃ (459 mg, 3.32 mmol) inacetone (2 mL) was heated at 150° C. for 900 s in a microwave. After theaddition of water, acetone was evaporated. The aqueous phase wasextracted with DCM. The organic phase was washed with brine, dried overMgSO₄, filtered and evaporated to yield 250 mg (1.03 mmol, 62%) of2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole.

108(B) 2-(But-3-ynyl)-2H-indazole and 1-(but-3-ynyl)-1H-indazole

TBAF (1.24 mL, 1.24 mmol) was added to a solution of2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole (250 mg, 1.03 mmol) in THF(5 mL) and the reaction mixture was stirred for 2 hours at roomtemperature. After the addition of water, the solvent was evaporated andthe aqueous phase was extracted with DCM. The organic phase was washedwith brine, dried over MgSO₄, filtered and evaporated. The crude residuewas purified by bulb-to-bulb distillation (0.2 mbar, 100-120° C.) toyield 160 mg (0.94 mmol, 91%) of 2-(but-3-ynyl)-2H-indazole and1-(but-3-ynyl)-1H-indazole.

108(C) 2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-indazole and1-(4-(pyridin-2-yl)but-3-ynyl)-1H-indazole

A solution of 2-(but-3-ynyl)-2H-indazole and 1-(but-3-ynyl)-1H-indazole(160 mg, 0.94 mmol) in DMF (0.5 mL) was added to a suspension of CuI(8.9 mg, 47 μmol), Et₃N (2.5 mL), Pd(PPh₃)₂Cl₂ (33 mg, 47 mmol), PPh₃(6.2 mg, 23 mmol) and 2-bromopyridine (149 mg, 0.94 mmol). The reactionmixture was heated at 120° C. for 900 s in a microwave. The reactionmixture was quenched with water, Et₃N was evaporated and the aqueousphase was extracted with DCM. The organic phase was washed with asaturated solution of NH₄OH, brine, dried over MgSO₄, filtered andevaporated. The crude residue was purified by flash chromatography(DCM/MeOH 99:1) and SCX column (DCM, DCM/MeOH 98:2, DCM/MeOH/NH₄OH95:4:1 to 94:4:2) to yield 6.8 mg (27 μmol, 3%) of2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole as a yellow solid and 4.6 mg(19 μmol, 2%) of 1-(4-(pyridin-2-yl)but-3-ynyl)-1H-indazole as an orangeoil.

2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-indazole

LCMS (RT): 3.53 min; MS (ES+) gave m/z: 248.2.

Rf (DCM/MeOH 98:2)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 3.18 (t, J=6.9, 2H), 4.69 (t, J=6.9, 2H),7.06-7.11 (m, 1H), 7.20-7.25 (m, 1H), 7.28-7.33 (2H), 7.59-7.64 (m, 1H),7.65-7.68 (m, 1H), 7.72 (dd, J=0.9 and 8.8, 1 H), 8.08 (d, J=0.9, 1H),8.57 (d, J=4.3, 1H).

1-(4-(Pyridin-2-yl)but-3-ynyl)-1H-indazole

LCMS (RT): 3.24 min; MS (ES+) gave m/z: 248.2.

Rf (DCM/MeOH 98:2)=0.03.

¹H-NMR (CDCl₃), δ (ppm): 3.07 (t, J=7.3, 2H), 4.68 (t, J=7.3, 2H),7.14-7.23 (3H), 7.36-7.42 (m, 1H), 7.51-7.55 (m, 1H), 7.57-7.62 (m, 1H),7.75 (d, J=8.1, 1H), 8.04 (s, 1H), 8.52-8.57 (m, 1H).

Example 109 2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleMethod A 109(A)2-(4-Trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]-triazole and1-(4-trimethylsilanyl-but-3-ynyl)-1H-benzo[d][1,2,3]triazole

The title compounds were prepared in accordance with the general methodof Example 108(A), from benzotriazole (116 mg, 0.97 mmol) to yield 157mg (0.64 mmol, 67%) of2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazole and1-(4-trimethylsilanyl-but-3-ynyl)-1H-benzo[d][1,2,3]triazole.

109(B) 2-(But-3-ynyl)-2H-benzo[d][1,2,3]-triazole and1-(but-3-ynyl)-1H-benzo[d][1,2,3]triazole

The title compounds were prepared in accordance with the general methodof Example 108(B), from2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazole and1-(4-trimethylsilanyl-but-3-ynyl)-1H-benzo[d][1,2,3]triazole (157 mg,0.64 mmol) to yield after bulb-to-bulb distillation (0.2 mbar, 80-100°C.), 90 mg (0.53 mmol, 83%) of 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazoleand 1-(but-3-ynyl)-1H-benzo[d][1,2,3]triazole.

109(C) 2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole and1-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d][1,2,3]triazole

The title compounds were prepared in accordance with the general methodof Example 108(C), from 90 mg (0.53 mmol) of2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole and1-(but-3-ynyl)-1H-benzo[d][1,2,3]triazole. The crude residue waspurified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 10 mg(42 mmol, 8%) of2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orangeoil with a purity of 82%. Another fraction yielded after SCX column(DCM, DCM/MeOH 98:2, DCM/MeOH/NH₄OH 95:4:1 to 94:4:2) 19 mg (76 μmol,14%) of 1-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d][1,2,3]triazole as anorange oil.

2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

LCMS (RT): 3.49 min; MS (ES+) gave m/z: 249.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.31 (t, J=7.6, 2H), 5.01 (t, J=7.6, 2H),7.19-7.24 (m, 1H), 7.35 (d, J=7.8, 1H), 7.41 (dd, J=3.1 and 6.6, 2H),7.60-7.65 (m, 1H), 7.89 (dd, J=3.1 and 6.6, 2H), 8.56 (d, J=4.1, 1 H).

1-(4-(Pyridin-2-yl)but-3-ynyl)-1H-benzo[d][1,2,3]triazole

LCMS (RT): 3.06 min; MS (ES+) gave m/z: 249.1.

Rf (DCM/MeOH 98:2)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 3.17 (t, J=7.1, 2H), 4.93 (t, J=7.1, 2H),7.17-7.23 (2H), 7.35-7.40 (m, 1H), 7.46-7.51 (m, 1H), 7.57-7.62 (m, 1H),7.65 (d, J=8.3, 1H), 8.08 (d, J=8.4, 1 H), 8.54 (d, J=4.6, 1H).

Method B 2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazolehydrochloride 109(D) 2-(But-3-ynyl)-2H-benzo[d][1,2,3]triazole

A solution of di-tert-butylazodicarboxylate (3.15 g, 13.4 mmol) in DCM(3 mL) was added dropwise over 30 min. at 0° C. to a suspension ofbenzotriazole (2.40 g, 1.50 mmol), but-3-yn-1-01 (940 mg, 13.4 mmol) andpolymer bounded triphenylphosphine (4.40 g, 16.8 mmol, 3 mmol/g) in DCM(3 mL). The reaction mixture was stirred at room temperature with apolymix agitation for 2 days and filtered through celite. The organicphase was washed with NH₄OH, brine, dried over MgSO₄, filtered andevaporated. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 571 mg (3.33 mmol, 25%) of2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.

LCMS (RT): 3.73 min; MS (ES+) gave m/z: 172.0.

Rf (cyclohexane/AcOEt 9:1)=0.3.

109(E) 2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (92 mg, 0.58 mmol) and2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol). Reactiontime: 3 hours. The crude residue was purified by flash chromatography(DCM/MeOH 99:1) to yield 90 mg of2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole.

Rf (DCM/MeOH 99:1)=0.1.

109(F) 2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[1,2,3]triazolehydrochloride

A solution of HCl (0.8 N, 906 μl) was added to a solution of2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole (90 mg) indioxane (5 mL). The reaction mixture was cooled in the fridge for 1hour. The resulting precipitate was filtered, washed with cold dioxaneand diethyl ether and dried to yield2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole hydrochloride(99 mg, 0.35 mmol, 60%) as a white solid.

LCMS (RT): 3.51 min; MS (ES+) gave m/z: 249.2.

¹H-NMR (CDCl₃), δ (ppm): 3.46 (t, J=7.0, 2H), 5.09 (t, J=7.0, 2H), 7.42(dd, J=3.1 and 6.6, 2H), 7.66 (d, J=8.0, 1H), 7.72-7.78 (m, 1H), 7.89(dd, J=3.1 and 6.6, 2H), 8.20-8.26 (m, 1H), 8.72 (d, J=4.6, 1 H).

Example 110 2-(4-(5-Phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine 110(A)5-Phenyl-1-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole and5-phenyl-2-(4-trimethylsilanyl-but-3-ynyl)-2H-pyrazole

The title compounds were prepared in accordance with the general methodof Example 108(A), from 3-phenyl-1H-pyrazole (200 mg, 1.39 mmol) toyield 300 mg (1.12 mmol, 81%) of5-phenyl-1-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole and5-phenyl-2-(4-trimethylsilanyl-but-3-ynyl)-2H-pyrazole.

110(B) 1-But-3-ynyl-5-phenyl-1H-pyrazole and2-but-3-ynyl-5-phenyl-2H-pyrazole

The title compounds were prepared in accordance with the general methodof Example 108(B), from5-phenyl-1-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole and5-phenyl-2-(4-trimethylsilanyl-but-3-ynyl)-2H-pyrazole (300 mg, 1.12mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 29 mg (0.15 mmol, 13%) of2-but-3-ynyl-5-phenyl-2H-pyrazole and 13 mg (66 mmol, 6%) of1-but-3-ynyl-5-phenyl-1H-pyrazole.

110(C) 2-(4-(5-Phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 108(C), from 30 mg (0.15 mmol) of2-but-3-ynyl-5-phenyl-2H-pyrazole. The crude residue was purified byflash chromatography (DCM/MeOH 99:1) and SCX column (DCM, DCM/MeOH 95:5,DCM/MeOH/NH₄OH 94:5:1 to 94:4:2) to yield 5 mg (18 mmol, 10%) of2-(4-(5-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid.

LCMS (RT): 3.86 min; MS (ES+) gave m/z: 274.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (DMSO[D]₆), δ (ppm): 3.01 (t, J=6.7, 2H), 4.39 (t, J=6.7, 2H),6.70 (d, J=2.3, 1H), 7.25-7.29 (m, 1H), 7.30-7.35 (m, 1H), 7.36-7.41(3H), 7.72-7.77 (m, 1H), 7.78-7.80 (2H), 7.87 (d, J=2.3, 1H), 8.48-8.51(m, 1H).

Example 111 2-(4-(3-Phenylisoxazol-5-yl)but-1-ynyl)pyridine 111(A)3-Phenyl-5-(4-trimethylsilanyl-but-3-ynyl)-isoxazole

The title compound was prepared in accordance with the general method ofExample 107(B), from 5-chloromethyl-3-phenyl-isoxazole (200 mg, 1.03mmol, reaction time: 1 day), to yield3-phenyl-5-(4-trimethylsilanyl-but-3-ynyl)-isoxazole (127 mg, 0.47 mmol,45%) as a white solid.

LCMS (RT): 5.59 min; MS (ES+) gave m/z: 270.1.

111(B) 5-But-3-ynyl-3-phenyl-isoxazole

The title compound was prepared in accordance with the general method ofExample 108(B), from3-phenyl-5-(4-trimethylsilanyl-but-3-ynyl)-isoxazole (127 mg, 0.47mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 67 mg (0.34 mmol, 72%) of5-but-3-ynyl-3-phenyl-isoxazole as a brown solid.

111(C) 2-(4-(3-Phenylisoxazol-5-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-iodo-pyridine (70 mg, 0.34 mmol) and5-but-3-ynyl-3-phenyl-isoxazole (67 mg, 0.34 mmol). Reaction time: 24hours. The crude residue was purified by flash chromatography (DCM/MeOH98:2) to yield 70 mg (0.26 mmol, 75%) of2-(4-(3-phenylisoxazol-5-yl)but-1-ynyl)pyridine as a brown solid.

LCMS (RT): 4.18 min; MS (ES+) gave m/z: 275.1.

¹H-NMR (CDCl₃), δ (ppm): 2.91 (t, J=7.4, 2H), 3.17 (t, J=7.4, 2H), 6.49(s, 1H), 7.19-7.23 (m, 1H), 7.35-7.39 (m, 1H), 7.41-7.48 (3H), 7.60-7.65(m, 1H), 7.77-7.83 (2H), 8.54-8.58 (m, 1H).

Example 112 2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 4-iodo-2-methyl-thiazole (120 mg, 0.53 mmol) and2-but-3-ynyl-benzo[d]thiazole (100 mg, 0.53 mmol, Example 35(A)). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt4:1) to yield 152 mg (0.28 mmol, 53%) of2-(4-(2-methylthiazol-4-yl)but-3-ynyl)benzo[d]thiazole as a yellowsolid.

LCMS (RT): 4.33 min; MS (ES+) gave m/z: 285.1.

Rf (cyclohexane/AcOEt 4:1)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 2.70 (s, 3H), 3.02 (t, J=7.5, 2H), 3.44 (t,J=7.5, 2H), 7.22 (s, 1H), 7.35-7.40 (m, 1H), 7.45-7.50 (m, 1H), 7.86(dd, J=0.5 and 8.0, 1H), 8.09 (d, J=8.0, 1H).

Example 113 2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-5-fluoro-pyridine (103 mg, 0.59 mmol) and2-but-3-ynyl-benzo[d]thiazole (110 mg, 0.59 mmol, Example 35(A)). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt4:1) to yield 78 mg (0.28 mmol, 47%) of2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a white solid.

LCMS (RT): 4.36 min; MS (ES+) gave m/z: 283.1.

Rf (cyclohexane/AcOEt 4:1)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.05 (t, J=7.4, 2H), 3.46 (t, J=7.4, 2H),7.32-7.41 (3H), 7.45-7.50 (m, 1H), 7.87 (dd, J=0.5 and 8.1, 1H), 8.00(d, J=8.1, 1H), 8.41 (d, J=2.8, 1H).

Example 114 2-(4-(6-Methylpyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-methyl-pyridine (110 mg, 0.64 mmol) and2-but-3-ynyl-benzo[d]thiazole (120 mg, 0.64 mmol, Example 35(A)). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt7:3) to yield 122 mg (0.44 mmol, 68%) of2-(4-(6-methylpyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a beige solid.

LCMS (RT): 3.53 min; MS (ES+) gave m/z: 279.1.

Rf (cyclohexane/AcOEt 7:3)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 2.55 (s, 3H), 3.04 (t, J=7.4, 2H), 3.46 (t,J=7.4, 2H), 7.08 (d, J=7.8, 1H), 7.21 (d, J=7.7, 1H), 7.35-7.40 (m, 1H),7.45-7.49 (m, 1H), 7.50-7.53 (m, 1H), 7.86 (d, J=8.0, 1H), 8.00 (d,J=8.0, 1H).

Example 115 2-(4-(6-Chloropyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 108(C), from 2,6-dichloro-pyridine (395 mg, 2.67 mmol) and2-but-3-ynyl-benzo[d]thiazole (100 mg, 0.53 mmol, Example 35(A)). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt4:1) to yield 31 mg (0.10 mmol, 19%) of2-(4-(6-chloropyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a white solid.

LCMS (RT): 4.73 min; MS (ES+) gave m/z: 299.1, 301.0.

Rf (cyclohexane/AcOEt 4:1)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.05 (t, J=7.5, 2H), 3.45 (t, J=7.5, 2H), 7.25(dd, J=0.7 and 8.0, 1H), 7.30 (dd, J=0.7 and 7.6, 1H), 7.36-7.41 (m,1H), 7.46-7.50 (m, 1H), 7.56-7.61 (m, 1H), 7.85-7.89 (m, 1H), 8.00 (d,J=8.1, 1H).

Example 1167-Chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole 116(A)2-Amino-6-chloro-3-fluoro-benzenethiol

The title compound was prepared in accordance with the general method ofExample 100(A), from 7-chloro-4-fluoro-benzothiazol-2-ylamine (1.1 g,5.4 mmol) to yield 2-amino-6-chloro-3-fluoro-benzenethiol (350 mg, 1.97mmol, 36%) as an orange oil.

116(B) 2-But-3-ynyl-7-chloro-4-fluoro-benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 8(A), from 2-amino-6-chloro-3-fluoro-benzenethiol (350 mg, 1.97mmol). Reaction time: 2 days. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 95:5) to yield 100 mg (0.42 mmol, 21%)of 2-but-3-ynyl-7-chloro-4-fluoro-benzo[d]thiazole as an orange oil.

LCMS (RT): 4.88 min; MS (ES+) gave m/z: 240.1.

116(C) 7-Chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (66 mg, 0.42 mmol) and2-but-3-ynyl-7-chloro-4-fluoro-benzo[d]thiazole (100 mg, 0.42 mmol). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt7:3) to yield 15 mg (47 mmol, 11%) of7-chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as abrown oil.

LCMS (RT): 4.59 min; MS (ES+) gave m/z: 317.1, 319.1.

Rf (cyclohexane/AcOEt 7:3)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.07 (t, J=7.3, 2H), 3.49 (t, J=7.3, 2H), 7.16(dd, J=8.6 and 9.8, 1H), 7.20-7.25 (m, 1H), 7.32 (dd, J=3.8 and 8.6,1H), 7.38-7.42 (m, 1H), 7.61-7.68 (m, 1H), 8.57 (s, 1H).

Example 117 2-(4-(6-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-fluoro-pyridine (66 mg, 0.37 mmol) and2-but-3-ynyl-benzo[d]thiazole (70 mg, 0.37 mmol, Example 35(A)). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt7:3) to yield 31 mg (0.11 mmol, 29%) of2-(4-(6-fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a white solid.

LCMS (RT): 4.51 min; MS (ES+) gave m/z: 283.1.

Rf (cyclohexane/AcOEt 7:3)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.05 (t, J=7.5, 2H), 3.46 (t, J=7.5, 2H), 6.87(dd, J=2.4 and 8.2, 1H), 7.26 (d, J=1.6, 1H), 7.36-7.41 (m, 1H),7.46-7.50 (m, 1H), 7.68-7.75 (m, 1H), 7.85-7.88 (m, 1H), 8.00 (d, J=8.1,1H).

Example 118 2-(4-(Pyridin-2-yl)but-3-ynyl)quinoline 118(A)2-(4-Trimethylsilanyl-but-3-ynyl)-quinoline

2-Methyl-quinoline (0.28 mL, 2.09 mmol) was added dropwise to a solutionof LDA (3.0 mL, 0.8 M in THF) in THF (3 mL) at −78° C. and the reactionmixture was stirred for 1 hour at −78° C. Then(3-bromo-prop-1-ynyl)-trimethyl-silane (0.39 mL, 2.51 mmol) was added tothe reaction mixture, the solution was stirred for 18 hours at roomtemperature and was quenched with water. The aqueous phase was extractedwith DCM. The organic phase was washed with water, dried over MgSO₄,filtered and evaporated. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 338 mg (1.33 mmol, 64%)of 2-(4-trimethylsilanyl-but-3-ynyl)-quinoline as a yellow solid.

LCMS (RT): 3.93 min; MS (ES+) gave m/z: 254.2.

118(B) 2-But-3-ynyl-quinoline

The title compound was prepared in accordance with the general method ofExample 108(B), from 2-(4-trimethylsilanyl-but-3-ynyl)-quinoline (803mg, 3.17 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 94:6 to 90:10) to yield 419 mg (2.31 mmol, 73%) of2-but-3-ynyl-quinoline as a yellow liquid.

LCMS (RT): 2.29 min; MS (ES+) gave m/z: 182.1.

118(C) 2-(4-(Pyridin-2-yl)but-3-ynyl)quinoline

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (87 mg, 0.55 mmol) and2-but-3-ynyl-quinoline (100 mg, 0.55 mmol). Reaction time: 120° C. for15 minutes. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 1:1) to yield 74 mg (0.29 mmol, 52%) of2-(4-(pyridin-2-yl)but-3-ynyl)quinoline as a yellow oil.

LCMS (RT): 2.56 min; MS (ES+) gave m/z: 259.2.

¹H-NMR (CDCl₃), δ (ppm): 3.02 (t, J=7.5, 2H), 3.34 (t, J=7.5, 2H),7.17-7.21 (m, 1H), 7.33 (d, J=7.8, 1H), 7.43 (d, J=8.4, 1H), 7.49-7.54(m, 1H), 7.58-7.63 (m, 1H), 7.69-7.74 (m, 1H), 7.81 (d, J=8.1, 1H), 8.08(d, J=8.4, 1H), 8.12 (d, J=8.4, 1H), 8.55 (d, J=4.7, 1H).

Example 119 2-(5-(Pyridin-2-yl)pent-4-ynyl)-2H-benzo[d][1,2,3]triazole119(A) 5-Pyridin-2-yl-pent-4-yn-1-ol

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (4.46 g, 28.2 mmol) and pent-4-yn-1-ol(2.50 g, 29.7 mmol). Reaction time: 14 hours. The crude residue waspurified by flash chromatography (DCM/MeOH 97:3) to yield 4.00 g (24.8mmol, 88%) of 5-pyridin-2-yl-pent-4-yn-1-ol as a brown oil.

119(B) 2-(5-Bromo-pent-1-ynyl)-pyridine

Br₂ (1.11 mL, 21.4 mmol) was added to a solution of triphenylphosphine(8.30 g, 30.7 mmol) in DCM (40 mL) at −5° C. A solution of5-pyridin-2-yl-pent-4-yn-1-ol (3.00, 18.6 mmol) in DCM (10 mL) was addeddropwise to the reaction mixture in order to maintain a temperaturelower than 5° C. The reaction mixture was stirred for 5 hours at −10° C.and was quenched with a saturated solution of NaHCO₃. The aqueous phasewas extracted with DCM. The resulting organic phase was washed withbrine, dried over MgSO₄, filtered and evaporated. The crude residue waspurified by flash chromatography (DCM/MeOH 99.5:0.5) to yield2-(5-bromo-pent-1-ynyl)-pyridine (1.20 g, 5.35 mmol, 29%) with a purityof 50%.

119(C) 2-(5-(Pyridin-2-yl)pent-4-ynyl)-2H-benzo[d][1,2,3]triazole and1-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d][1,2,3]triazole

The title compounds were prepared in accordance with the general methodof Example 108(A), from 2-(5-bromo-pent-1-ynyl)-pyridine (298 mg, 0.66mmol) and benzotriazole (72 mg, 0.60 mmol). The crude product waspurified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield2-(5-(pyridin-2-yl)pent-4-ynyl)-2H-benzo[d][1,2,3]triazole (27 mg, 0.1mmol) as an orange oil and1-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d][1,2,3]triazole (27 mg, 0.1mmol) as an orange solid.

2-(5-(pyridin-2-yl)pent-4-ynyl)-2H-benzo[d][1,2,3]triazole

LCMS (RT): 3.46 min; MS (ES+) gave m/z: 263.2.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 2.43-2.50 (2H), 2.58 (t, J=6.8, 2H), 4.93 (t,J=6.8, 2H), 7.18-7.22 (m, 1H), 7.33-7.36 (m, 1H), 7.39 (dd, J=3.1 and6.6, 2H), 7.59-7.64 (m, 1H), 7.87 (dd, J=3.1 and 6.6, 2H), 8.53-8.56 (m,1H).

1-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d][1,2,3]triazole

LCMS (RT): 3.14 min; MS (ES+) gave m/z: 263.2.

Rf (DCM/MeOH 98:2)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 2.37-2.41 (2H), 2.52 (t, J=6.7, 2H), 4.85 (t,J=6.7, 2H), 7.21-7.25 (m, 1H), 7.35-7.40 (2H), 7.46-7.51 (m, 1H),7.62-7.66 (2H), 8.04-8.08 (m, 1H), 8.58 (d, J=4.4, 1H).

Example 1202-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was prepared in accordance with the general method ofExample 1, from 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(70 mg, 0.37 mmol, Example 39(A)) and 2-bromo-6-(fluoromethyl)pyridine(78 mg, 0.41 mmol, Example 190(E)). The crude residue was purified byflash chromatography (DCM/MeOH 98:2) to yield 20 mg (67 μmol, 18%) of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-oneas an orange solid (M.P.=106-107° C.).

LCMS (RT): 3.08 min; MS (ES+) gave m/z: 297.0.

Rf (DCM/MeOH 98:2)=0.05.

¹H-NMR (CDCl₃), δ (ppm): 3.00 (t, J=7.2, 2H), 4.29 (t, J=7.2, 2H),5.36-5.54 (m, 2H), 6.46-6.52 (m, 1H), 7.09 (dd, J=1.2 and 3.6, 2H), 7.33(d, J=7.8, 1H), 7.38 (d, J=7.8, 1H), 7.66-7.72 (m, 1H), 7.73-7.78 (m,1H).

Example 121 2-(4-(1-Methyl-1H-pyrazol-3-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 108(C), from 3-bromo-1-methyl-1H-pyrazole (100 mg, 0.62 mmol)and 2-but-3-ynyl-benzo[d]thiazole (233 mg, 1.24 mmol, Example 35(A)).The crude residue was purified by flash chromatography(cyclohexane/AcOEt 7:3) to yield 35 mg (0.13 mmol, 21%) of2-(4-(1-methyl-1H-pyrazol-3-yl)but-3-ynyl)benzo[d]thiazole as a brownsemi-solid.

LCMS (RT): 3.96 min; MS (ES+) gave m/z: 268.1.

Rf (cyclohexane/AcOEt 7:3)=0.2.

Example 122 2-(4-(4-Phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine 122(A)4-Phenyl-1-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole

The title compound was prepared in accordance with the general method ofExample 108(A), from 4-phenyl-1H-pyrazole (250 mg, 1.73 mmol) to yield380 mg (1.42 mmol, 82%) of4-phenyl-1-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole.

122(B) 1-But-3-ynyl-4-phenyl-1H-pyrazole

The title compound was prepared in accordance with the general method ofExample 108(B), from4-phenyl-1-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole (380 mg, 1.42mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 80 mg (0.41 mmol, 29%) of1-but-3-ynyl-4-phenyl-1H-pyrazole.

122(C) 2-(4-(4-Phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 80 mg (0.41 mmol) of 1-but-3-ynyl-4-phenyl-1H-pyrazole.The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to98:2) and SCX column (DCM, DCM/MeOH 97:3, DCM/MeOH/NH₄OH 94:5:1) toyield 2 mg (7 mmol, 2%) of2-(4-(4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine.

LCMS (RT): 3.76 min; MS (ES+) gave m/z: 274.1.

Rf (DCM/MeOH 98:2)=0.3.

Example 123 7-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole 123(A)7-Chloro-1H-indazole

A solution of 2-chloro-6-methyl-phenylamine (500 mg, 3.53 mmol) in H₂SO₄(1.37 mL) was diluted by adding over 15 min. 2 mL of water in order tomaintain a temperature below 90° C. Then the reaction mixture was cooledto 5-10° C. and a solution of sodium nitrite (246 mg, 3.57 mmol) inwater (1 mL) was added over 2 hours. The resulting diazonium solutionwas then added to a solution of sodium acetate (5.21 g, 63.6 mmol) inwater (20 mL) at a temperature maintained between 65 to 75° C. Theresulting precipitate was filtered and treated with a solution of NaOH(6.00 g) in water (100 mL) at 95-100° C. The aqueous phase was separatedwhile hot from the small amount of black tarry by-products, cooled to50-60° C. and acidified with HCl (37%, 12.5 mL). The reaction mixturewas cooled down to room temperature, the resulting precipitate wasfiltered, was washed thrice with cold water and was dried under vacuumto yield 7-chloro-1H-indazole (220 mg, 1.44 mmol, 41%) as a white solid.

123(B) 7-Chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and7-chloro-1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole

The title compounds were prepared in accordance with the general methodof Example 108(A), from 7-chloro-1H-indazole (220 mg, 1.44 mmol) toyield 250 mg (0.90 mmol, 63%) of7-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and7-chloro-1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole.

123(C) 2-But-3-ynyl-7-chloro-2H-indazole

The title compound was prepared in accordance with the general method ofExample 108(B), from7-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and7-chloro-1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole (250 mg, 0.90mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 44 mg (0.21 mmol, 23%) of2-(but-3-ynyl)-7-chloro-2H-indazole as an orange oil.

123(D) 7-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (36 mg, 0.23 mmol) and2-but-3-ynyl-7-chloro-2H-indazole (44 mg, 0.21 mmol). Reaction time: 1day. The crude residue was purified by flash chromatography (DCM/MeOH98:2) to yield 11 mg (41 μmol, 19%) of7-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown oil.

Rf (DCM/MeOH 98:2)=0.05.

LCMS (RT): 4.13 min; MS (ES+) gave m/z: 282.1.

¹H-NMR (CDCl₃), δ (ppm): 3.06 (t, J=7.5, 2H), 5.07 (t, J=7.5, 2H),7.05-7.10 (m, 1H), 7.18-7.22 (m, 1H), 7.27-7.30 (m, 1H), 7.37 (dd, J=0.9and 7.5, 1H), 7.58-7.63 (m, 1H), 7.64 (dd, J=0.9 and 8.0, 1H), 8.04 (s,1H), 8.52-8.56 (m, 1H).

Example 124 2-(6-(Pyridin-2-yl)hex-5-ynyl)-2H-benzo[d][1,2,3]triazole124(A) 6-Pyridin-2-yl-hex-5-yn-1-ol

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (6.44 g, 40.8 mmol) and hex-5-yn-1-ol(4.00 g, 40.8 mmol). The crude residue was purified by flashchromatography (DCM/MeOH 1:1) to yield 5.56 g (31.7 mmol, 78%) of6-pyridin-2-yl-hex-5-yn-1-ol as an orange oil.

124(B) 2-(6-Bromo-hex-1-ynyl)-pyridine

The title compound was prepared in accordance with the general method ofExample 119(B), from 6-pyridin-2-yl-hex-5-yn-1-ol (1.00 g, 5.77 mmol).The crude residue was purified by flash chromatography(cyclohexane/AcOEt 1:1) to yield 2-(6-bromo-hex-1-ynyl)-pyridine (0.74g, 3.10 mmol, 54%) as an orange oil.

LCMS (RT): 3.94 min; MS (ES+) gave m/z: 240.2.

124(C) 1-(6-(Pyridin-2-yl)hex-5-ynyl)-1H-benzo[d][1,2,3]triazole and2-(6-(pyridin-2-yl)hex-5-ynyl)-2H-benzo[d][1,2,3]triazole

The title compounds were prepared in accordance with the general methodof Example 109(D), from 2-(6-bromo-hex-1-ynyl)-pyridine (250 mg, 1.05mmol) and benzotriazole (125 mg, 1.05 mmol). The crude product waspurified by flash chromatography (cyclohexane/AcOEt 3:2) to yield2-(6-(pyridin-2-yl)hex-5-ynyl)-2H-benzo[d][1,2,3]triazole (38 mg, 0.14mmol, 13%) as a brown oil and (cyclohexane/AcOEt 1:1) to yield1-(6-(pyridin-2-yl)hex-5-ynyl)-1H-benzo[d][1,2,3]triazole (48 mg, 0.17mmol, 16%) as a brown oil.

2-(6-(Pyridin-2-yl)hex-5-ynyl)-2H-benzo[d][1,2,3]triazole

LCMS (RT): 3.93 min; MS (ES+) gave m/z: 277.2.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 1.68-1.73 (2H), 2.30-2.36 (2H), 2.53 (t, J=7.0,2H), 4.81 (t, J=7.0, 2H), 7.19 (ddd, J=1.1, 4.9 and 7.6, 1H), 7.34-7.41(3H), 7.59-7.64 (m, 1H), 7.84-7.89 (2H), 8.55 (d, J=4.3, 1H).

1-(6-(Pyridin-2-yl)hex-5-ynyl)-1H-benzo[d][1,2,3]triazole

LCMS (RT): 3.43 min; MS (ES+) gave m/z: 277.2.

Rf (cyclohexane/AcOEt 1:1)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 1.65-1.73 (2H), 2.21-2.28 (2H), 2.53 (t, J=7.0,2H), 4.72 (t, J=7.0, 2H), 7.20 (ddd, J=1.1, 4.9 and 7.6, 1H), 7.34 (d,J=7.8, 1H), 7.35-7.40 (m, 1H), 7.45-7.50 (m, 1H), 7.54-7.68 (m, 1H),7.59-7.64 (m, 1H), 8.05-8.09 (m, 1H), 8.55 (d, J=4.4, 1H).

Example 125 2-(6-(Pyridin-2-yl)hex-5-ynyl)-2H-indazole

The title compounds were prepared in accordance with the general methodof Example 109(D), from 2-(6-bromo-hex-1-ynyl)-pyridine (250 mg, 1.05mmol, Example 124(B)) and indazole (124 mg, 1.05 mmol). The crudeproduct was purified by flash chromatography

(cyclohexane/AcOEt 75:25) to yield2-(6-(pyridin-2-yl)hex-5-ynyl)-2H-indazole (26 mg, 94 μmol, 9%) as abrown oil and (cyclohexane/AcOEt 1:1) to yield1-(6-(pyridin-2-yl)hex-5-ynyl)-1H-indazole (15 mg, 54 μmol, 5%) as abrown oil.

2-(6-(Pyridin-2-yl)hex-5-ynyl)-2H-indazole

LCMS (RT): 3.93 min; MS (ES+) gave m/z: 276.2.

Rf (cyclohexane/AcOEt 1:1)=0.3.

¹H-NMR (CDCl₃), δ (ppm): 1.62-1.69 (2H), 2.11-2.18 (2H), 2.49 (t, J=7.0,2H), 4.46 (t, J=7.0, 2H), 7.12-7.17 (m, 1H), 7.19 (ddd, J=1.1, 4.9 and7.6, 1H), 7.32-7.35 (m, 1H), 7.35-7.39 (m, 1H), 7.44 (dd, J=0.9 and 8.5,1H), 7.58-7.63 (m, 1H), 7.72-7.76 (m, 1H), 8.00 (d, J=0.9, 1H),8.52-8.56 (m, 1H).

1-(6-(Pyridin-2-yl)hex-5-ynyl)-1H-indazole

LCMS (RT): 3.54 min; MS (ES+) gave m/z: 276.2.

Rf (cyclohexane/AcOEt 1:1)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 1.64-1.71 (2H), 2.20-2.27 (2H), 2.51 (t, J=7.0,2H), 4.50 (t, J=7.0, 2H), 7.09 (ddd, J=0.8, 6.6 and 8.4, 1H), 7.20 (ddd,J=1.1, 4.9 and 7.6, 1H), 7.28-7.31 (m, 1H), 7.36 (d, J=7.6, 1H),7.59-7.64 (m, 1H), 7.64-7.67 (m, 1H), 7.70-7.73 (m, 1H), 7.95 (d, J=0.8,1H), 8.55 (d, J=4.3, 1H).

Example 126 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoline

The title compound was prepared in accordance with the general method ofExample 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (157 mg, 0.83mmol) and 2-but-3-ynyl-quinoline (150 mg, 0.83 mmol, Example 118(B)).Microwave conditions: 120° C. for 15 minutes. The crude residue waspurified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 127 mg(0.44 mmol, 53%) of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoline as an orangesolid (M.P.=70.2-74.3° C.).

LCMS (RT): 2.98 min; MS (ES+) gave m/z: 291.2.

¹H-NMR (CDCl₃), δ (ppm): 3.03 (t, J=7.5, 2H), 3.33 (t, J=7.5, 2H),5.40-5.53 (m, 2H), 7.29 (d, J=7.8, 1H), 7.38 (d, J=7.8, 1H), 7.40 (d,J=8.4, 1H), 7.49-7.54 (m, 1H), 7.65-7.70 (m, 1H), 7.70-7.74 (m, 1H),7.81 (d, J=8.1, 1H), 8.07 (d, J=8.4, 1H), 8.11 (d, J=8.4, 1H).

Example 1275-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole127(A) 5-Fluoro-1H-benzo[d][1,2,3]triazole

A solution of sodium nitrite (284 mg, 4.12 mmol) in water (1 mL) wasadded to a solution of 4-fluoro-benzene-1,2-diamine (520 mg, 4.12 mmol)in acetic acid (0.50 mL) and water (2.50 mL) at 0° C. The reactionmixture was stirred for few minutes at 50° C. and 1 hour at 0° C. Theprecipitate was filtered, washed with cold water and dried to yield5-fluoro-1H-benzo[d][1,2,3]triazole (565 mg, 3.50 mmol, 85%).

127(B)5-Fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazole

(4-Bromo-but-1-ynyl)-trimethyl-silane (294 mg, 1.43 mmol) was added to asolution of 5-fluoro-1H-benzo[d][1,2,3]triazole (187 mg, 1.36 mmol) in asolution of NaOH (2N, 955 μL). The reaction mixture was heated at 100°C. for 14 hours, then it was cooled down and was extracted with DCM. Theorganic phase was washed with water, brine, dried over MgSO₄, filteredand evaporated to yield 355 mg (1.36 mmol)5-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazoleincluding the two others isomers.

127(C) 2-But-3-ynyl-5-fluoro-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 108(B), from5-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazole(355 mg, 1.36 mmol). The crude residue was purified by flashchromatography (cyclohexane/AcOEt 9:1) to yield 27 mg (0.14 mmol, 10%)of 2-(but-3-ynyl)-5-fluoro-2H-benzo[d][1,2,3]triazole.

Rf (cyclohexane/AcOEt 9:1)=0.3.

127(D)5-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (20 mg, 0.13 mmol) and2-(but-3-ynyl)-5-fluoro-2H-benzo[d][1,2,3]triazole (24 mg, 0.13 mmol).Reaction time: 1 day. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) and SCX column (DCM, DCM/MeOH 98:2 toDCM/MeOH/NH₄OH 95:4:1) to yield 7.6 mg (26 mmol, 21%) of5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as ayellow solid.

Rf (DCM/MeOH 97:3)=0.2.

LCMS (RT): 3.71 min; MS (ES+) gave m/z: 267.2.

¹H-NMR (CDCl₃), δ (ppm): 3.29 (t, J=7.5, 2H), 4.97 (t, J=7.5, 2H),7.18-7.24 (2H), 7.32-7.36 (m, 1H), 7.47 (ddd, J=0.6, 2.4 and 8.7, 1H),7.59-7.65 (m, 1H), 7.86 (ddd, J=0.6, 4.8 and 9.3, 1H), 8.53-8.57 (m,1H).

Example 128 2-(4-(6-Methylpyridin-2-yl)but-3-ynyl)quinoline

The title compound was prepared in accordance with the general method ofExample 108(C), from 2-bromo-6-methyl-pyridine (209 mg, 1.21 mmol) and2-but-3-ynyl-quinoline (220 mg, 1.21 mmol Example 118(B)). Microwaveconditions: 120° C. for 15 minutes. The crude residue was purified byflash chromatography (cyclohexane/AcOEt 1:1) to yield 98 mg (0.36 mmol,30%) of 2-(4-(6-methylpyridin-2-yl)but-3-ynyl)quinoline as a yellow oil.

LCMS (RT): 2.44 min; MS (ES+) gave m/z: 273.2.

¹H-NMR (CDCl₃), δ (ppm): 2.54 (s, 3H), 3.01 (t, J=7.5, 2H), 3.32 (t,J=7.5, 2H), 7.05 (d, J=7.7, 1H), 7.15 (d, J=7.7, 1H), 7.41 (d, J=8.4,1H), 7.46-7.50 (m, 1H), 7.49-7.54 (m, 1H), 7.68-7.73 (m, 1H), 7.78-7.82(m, 1H), 8.07 (d, J=8.4, 1H), 8.11 (d, J=8.4, 1H).

Example 129 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline129(A) 2-(4-Trimethylsilanyl-but-3-ynyl)-quinoxaline

The title compound was prepared in accordance with the general method ofExample 118(A), from 2-methyl-quinoxaline (0.47 mL, 3.47 mmol). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt85:15) to yield 291 mg (1.11 mmol, 32%) of2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline as an orange oil.

LCMS (RT): 5.16 min; MS (ES+) gave m/z: 255.1.

129(B) 2-But-3-ynyl-quinoxaline

The title compound was prepared in accordance with the general method ofExample 108(B), from 2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline (291mg, 1.11 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 94:6 to 90:10) to yield 120 mg (0.66 mmol, 71%) of2-but-3-ynyl-quinoxaline as a yellow liquid.

LCMS (RT): 3.59 min; MS (ES+) gave m/z: 183.1.

129(C) 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline

The title compound was prepared in accordance with the general method ofExample 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (104 mg, 0.55mmol) and 2-but-3-ynyl-quinoxaline (100 mg, 0.55 mmol). Microwaveconditions: 120° C. for 15 minutes. The crude residue was purified byflash chromatography (cyclohexane/AcOEt 3:2) to yield 116 mg (0.40 mmol,72%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline as anorange solid (M.P.: 136° C. dec.).

LCMS (RT): 3.96 min; MS (ES+) gave m/z: 292.1.

¹H-NMR (CDCl₃), δ (ppm): 3.06 (t, J=7.4, 2H), 3.37 (t, J=7.4, 2H),5.40-5.53 (m, 2H), 7.26-7.30 (m, 1H), 7.39 (d, J=7.8, 1H), 7.66-7.71 (m,1H), 7.72-7.81 (2H), 8.06-8.12 (2H), 8.86 (s, 1H).

Example 1302-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazolehydrochloride 130(A)2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (111 mg, 0.58 mmol,Example 190(E)) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg,0.58 mmol, Example 109(D)). Reaction time: 3 hours. The crude residuewas purified by flash chromatography (DCM/MeOH 99:1) to yield 61 mg(0.22 mmol, 37%) of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a grey solid.

Rf (DCM/MeOH 98:2)=0.2.

LCMS (RT): 4.06 min; MS (ES+) gave m/z: 281.1.

¹H-NMR, CDCl₃, δ (ppm): 3.31 (t, J=7.5, 2H), 5.00 (t, J=7.5, 2H),5.40-5.53 (m, 2H), 7.29 (d, J=7.8, 1H), 7.39-7.43 (3H), 7.68-7.72 (m,1H), 7.88 (dd, J=3.0 and 6.6, 2H).

130(B)2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazolehydrochloride

The title compound was prepared in accordance with the general method ofExample 109(F), from2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole(60 mg, 0.21 mmol) to yield2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazolehydrochloride (33 mg, 0.11 mmol, 48%) as a white solid (M.P.:172.5-173.5° C.).

LCMS (RT): 4.08 min; MS (ES+) gave m/z: 281.2.

¹H-NMR CDCl₃, δ (ppm): 1.72-2.80 (br. s, 1H), 3.36 (t, J=7.0, 2H), 5.03(t, J=7.0, 2H), 5.64-5.78 (m, 2H), 7.38-7.42 (3H), 7.58 (d, J=8.0, 1H),7.87 (dd, J=3.0 and 6.5, 2H), 7.89-7.94 (m, 1H).

Example 1314,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazolehydrochloride 131(A) 5,7-Difluoro-1H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 127(A), from 3,5-difluorobenzene-1,2-diamine (520 mg, 3.61 mmol)to yield 5,7-difluoro-1H-benzo[d][1,2,3]triazole (492 mg, 3.17 mmol,88%) as a dark solid.

131(B) 2-(But-3-ynyl)-4,6-difluoro-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 5,7-difluoro-1H-benzo[d][1,2,3]triazole (271 mg,1.75 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 100 mg (0.48 mmol, 33%) of2-(but-3-ynyl)-4,6-difluoro-2H-benzo[d][1,2,3]triazole.

Rf (DCM/MeOH 9:1)=0.3.

131(C)4,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.27 mmol) and2-(but-3-ynyl)-4,6-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24mmol). Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 45 mg (0.14 mol, 53%) of4,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a brown oil.

Rf (DCM/MeOH 98:2)=0.2.

LCMS (RT): 4.44 min; MS (ES+) gave m/z: 317.1.

¹H-NMR, δ (ppm): 3.31 (t, J=7.3, 2H), 4.99 (t, J=7.3, 2H), 5.42 (s, 1H),5.51 (s, 1H), 6.89-6.95 (m, 1H), 7.28-7.33 (2H), 7.41 (d, J=7.8, 1H),7.68-7.73 (m, 1H).

131(D)4,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazolehydrochloride

The title compound was prepared in accordance with the general method ofExample 109(F), from4,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole(45 mg) to yield the corresponding hydrochloride (50 mg, 0.14 mmol) as awhite solid (M.P.: 128-130° C.).

LCMS (RT): 4.46 min; MS (ES+) gave m/z: 317.1.

¹H-NMR, δ (ppm): 3.40 (t, J=7.1, 2H), 5.07 (t, J=7.1, 2H), 5.40-5.53 (m,2H), 6.89-6.95 (m, 1H), 7.31 (dd, J=2.0 and 8.2, 1H), 7.54 (d, J=7.9,1H), 7.74 (d, J=7.9, 1H), 8.08-8.13 (m, 1H).

Example 1324,5-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazolehydrochloride 132(A) 4,5-Difluoro-1H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 127(A), from 3,4-difluorobenzene-1,2-diamine (490 mg, 3.40 mmol)to yield 4,5-difluoro-1H-benzo[d][1,2,3]triazole (485 mg, 3.13 mmol,92%).

132(B) 2-(But-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 4,5-difluoro-1H-benzo[d][1,2,3]triazole (266 mg,1.71 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 100 mg (0.48 mmol, 34%) of2-(but-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole.

Rf (DCM/MeOH 9:1)=0.2.

132(C)4,5-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.27 mmol) and2-(but-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24mmol). Reaction time: 13 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 45 mg (0.14 mmol, 59%) of4,5-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole.

Rf (DCM/MeOH 98:2)=0.2.

LCMS (RT): 4.43 min; MS (ES+) gave m/z: 317.1.

¹H-NMR, δ (ppm): 3.31 (t, J=7.3, 2H), 5.00 (t, J=7.3, 2H), 5.40-5.53 (m,2H), 7.26-7.32 (2H), 7.41 (d, J=7.8, 1H), 7.64 (dd, J=1.3, 3.7 and 9.2,1H), 7.68-7.73 (m, 1H).

132(D)4,5-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazolehydrochloride

The title compound was prepared in accordance with the general method ofExample 109(F), from4,5-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole(45 mg, 0.14 mmol) to yield the corresponding hydrochloride (50 mg, 0.14mmol) as a white solid (M.P.: 157-159° C.).

LCMS (RT): 4.41 min; MS (ES+) gave m/z: 317.1.

¹H-NMR (DMSO[D]₆), δ (ppm): 3.32 (t, J=6.7, 2H), 5.04 (t, J=6.7, 2H),5.32-5.45 (m, 2H), 5.40-5.70 (br. s, 1H), 7.31 (d, J=7.8, 1H), 7.42 (d,J=7.8, 1H), 7.55-7.61 (m, 1H), 7.80-7.85 (m, 1H), 7.89 (ddd, J=0.9, 3.8and 9.3, 1H).

Example 133 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole

The title compound was prepared in accordance with the general method ofExample 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (204 mg, 1.07mmol) and 2-but-3-ynyl-2H-indazole (183 mg, 1.07 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 3:2) toyield 50 mg (0.18 mmol, 17%) of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as acolorless oil.

¹H-NMR (CDCl₃), δ (ppm): 3.07 (t, J=7.3, 2H), 4.68 (t, J=7.3, 2H),5.40-5.53 (m, 2H), 7.12 (d, J=7.7, 1H), 7.14-7.19 (m, 1H), 7.37-7.41(2H), 7.52 (d, J=8.5, 1H), 7.64-7.69 (m, 1H), 7.75 (d, J=8.1, 1H), 8.04(s, 1H).

Example 1342-(4-(6-(Difluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole134(A) 2-Bromo-6-difluoromethyl-pyridine

DAST (0.99 mL, 8.06 mmol) was added dropwise to a solution of6-bromo-pyridine-2-carbaldehyde (1.00 g, 5.38 mmol) in DCM (28 mL) at 0°C. The reaction mixture was stirred for 24 hours at room temperature,quenched by the addition of saturated aqueous solution of NaHCO₃ andextracted twice with DCM. The organic phase was washed with water, driedover MgSO₄, filtered and evaporated. The crude residue was purified byflash chromatography (cyclohexane/AcOEt 9:1) to yield 0.74 g (3.56 mmol,66%) of 2-bromo-6-difluoromethyl-pyridine as a yellow oil.

134(B)2-(4-(6-(Difluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(difluoromethyl)-pyridine (121 mg, 0.58 mmol)and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol,Example 109(D)). Reaction time: 2 hours. The crude residue was purifiedby preparative chromatography plate (DCM/MeOH 99:1) to yield 15 mg (49μmol, 8%) of2-(4-(6-(difluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a white solid (M.P.: 101.8-102.9° C.).

LCMS (RT): 4.31 min; MS (ES+) gave m/z: 299.1.

¹H-NMR CDCl₃, δ (ppm): 3.32 (t, J=7.4, 2H), 5.01 (t, J=7.4, 2H),6.49-6.71 (m, 1H), 7.38-7.45 (3H), 7.58 (d, J=7.7, 1H), 7.76-7.81 (m,1H), 7.89 (dd, J=3.1 and 6.6, 2H).

Example 1354,6-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole135(A) 5,7-Difluoro-1H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 127(A), from 3,5-difluorobenzene-1,2-diamine (520 mg, 3.61 mmol)to yield 5,7-difluoro-1H-benzo[d][1,2,3]triazole (492 mg, 3.17 mmol,88%).

135(B) 2-(But-3-ynyl)-4,6-difluoro-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 5,7-difluoro-1H-benzo[d][1,2,3]triazole (271 mg,1.75 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 100 mg (0.48 mmol, 33%) of2-(but-3-ynyl)-4,6-difluoro-2H-benzo[d][1,2,3]triazole.

Rf (cyclohexane/AcOEt 9:1)=0.3.

135(C)4,6-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (42 mg, 0.26 mmol) and2-(but-3-ynyl)-4,6-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24mmol). Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 31 mg (0.11 mmol, 46%) of4,6-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a yellow solid.

Rf (DCM/MeOH 99:1)=0.1.

LCMS (RT): 4.03 min; MS (ES+) gave m/z: 285.1.

¹H-NMR (CDCl₃), δ (ppm): 3.30 (t, J=7.4, 2H), 4.99 (t, J=7.4, 2H),6.88-6.94 (m, 1H), 7.18-7.24 (m, 1H), 7.32 (dd, J=2.0 and 8.3, 1H), 7.35(d, J=7.8, 1H), 7.60-7.65 (m, 1H), 8.55 (d, J=4.8, 1H).

Example 1364,5-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole136(A) 4,5-Difluoro-1H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 127(A), from 3,4-difluorobenzene-1,2-diamine (490 mg, 3.40 mmol)to yield 4,5-difluoro-1H-benzo[d][1,2,3]triazole (485 mg, 3.13 mmol,92%).

136(B) 2-(But-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D) from 4,5-difluoro-1H-benzo[d][1,2,3]triazole (266 mg,1.71 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 100 mg (0.48 mmol, 33%) of2-(but-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole.

Rf (DCM/MeOH 9:1)=0.2.

136(C)4,5-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (42 mg, 0.26 mmol) and2-(but-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24mmol). Reaction time: 13 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 41 mg (0.14 mmol, 60%) of4,5-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a yellow solid.

Rf (DCM/MeOH 99:1)=0.1.

LCMS (RT): 4.01 min; MS (ES+) gave m/z: 285.2.

¹H-NMR (CDCl₃), δ (ppm): 3.31 (t, J=7.4, 2H), 5.00 (t, J=7.4, 2H),7.20-7.24 (m, 1H), 7.26-7.32 (m, 1H), 7.35 (d, J=7.8, 1H), 7.60-7.66(2H), 8.55 (d, J=4.8, 1H).

Example 1372-(4-(6-Methylpyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-methylpyridine (55 mg, 0.32 mmol) and2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (50 mg, 0.29 mmol, Example109(D)). Reaction time: 13 hours. The crude residue was purified byflash chromatography (DCM/MeOH 99:1) to yield 40 mg (0.15 mmol, 53%) of2-(4-(6-methylpyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as ayellow solid.

Rf (DCM/MeOH 98:2)=0.2.

LCMS (RT): 3.23 min; MS (ES+) gave m/z: 263.2.

¹H-NMR (CDCl₃), δ (ppm): 2.54 (s, 3H), 3.30 (t, J=7.6, 2H), 5.00 (t,J=7.6, 2H), 7.08 (d, J=7.7, 1H), 7.17 (d, J=7.7, 1H), 7.40 (dd, J=3.1and 6.6, 2H), 7.48-7.53 (m, 1H), 7.88 (dd, J=3.1 and 6.6, 2H).

Example 1382-(4-(3-Fluoropyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-chloro-3-fluoropyridine (42 mg, 0.32 mmol) and2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (50 mg, 0.29 mmol, Example109(D)). Reaction time: 13 hours. The crude residue was purified byflash chromatography (DCM/MeOH 99:1) to yield 21 mg (80 mmol, 27%) of2-(4-(3-fluoropyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as ayellow solid.

Rf (DCM/MeOH 98:2)=0.1.

LCMS (RT): 3.91 min; MS (ES+) gave m/z: 267.2.

¹H-NMR (CDCl₃), δ (ppm): 3.37 (t, J=7.6, 2H), 5.03 (t, J=7.6, 2H),7.23-7.29 (2H), 7.38-7.43 (2H), 7.89 (dd, J=3.0 and 6.6, 2H), 8.35-8.40(m, 1H).

Example 1395-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole139(A) 5-Fluoro-1H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 127(A), from 4-fluorobenzene-1,2-diamine (500 mg, 3.96 mmol) toyield 5-fluoro-1H-benzo[d][1,2,3]triazole (376 mg, 2.74 mmol, 69%) as adark solid.

139(B) 2-(But-3-ynyl)-5-fluoro-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 5-fluoro-1H-benzo[d][1,2,3]triazole (360 mg, 2.63mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 137 mg (0.72 mmol, 32%) of2-(but-3-ynyl)-5-fluoro-2H-benzo[d][1,2,3]triazole.

Rf (cyclohexane/AcOEt 9:1)=0.3.

139(C)5-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (55 mg, 0.29 mmol) and2-(but-3-ynyl)-5-fluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.26 mmol).Reaction time: 13 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 50 mg (0.17 mmol, 64%) of5-fluoro-2-(4-(6-fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a yellow solid.

Rf (DCM/MeOH 99:1)=0.1.

LCMS (RT): 4.26 min; MS (ES+) gave m/z: 299.2.

¹H-NMR (CDCl₃), δ (ppm): 3.29 (t, J=7.4, 2H), 4.97 (t, J=7.4, 2H),5.40-5.53 (m, 2H), 7.18-7.24 (m, 1H), 7.28 (d, J=7.8, 1H), 7.41 (d,J=7.8, 1H), 7.47 (ddd, J=0.5, 2.3 and 8.7, 1H), 7.68-7.72 (m, 1H), 7.86(ddd, J=0.5, 4.8 and 9.2, 1H).

Example 140 2-(4-(4-(4-Fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine140(A) 1-But-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 4-(4-fluoro-phenyl)-1H-pyrazole (255 mg, 1.57mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 223 mg (1.04 mmol, 73%) of1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole.

140(B) 2-(4-(4-(4-Fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 50 mg (0.23 mmol) of1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole. Reaction time: 13 hours.The crude residue was purified by flash chromatography (DCM/MeOH 98:2)and SCX column (DCM, DCM/MeOH 95:5, DCM/MeOH/NH₄OH 94:5:1) to yield 2 mg(7 mmol, 3%) of244-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellowsolid.

LCMS (RT): 3.88 min; MS (ES+) gave m/z: 292.2.

Rf (DCM/MeOH 98:2)=0.3.

¹H-NMR (CDCl₃), δ (ppm): 3.05 (t, J=6.9, 2H), 4.42 (t, J=6.9, 2H),7.03-7.27 (2H), 7.19-7.24 (m, 1H), 7.34 (d, J=7.8, 1H), 7.41-7.45 (2H),7.58-7.64 (m, 1H), 7.76 (d, J=8.3, 2H), 8.55-8.59 (m, 1H).

Example 1412-(4-(2-Methylthiazol-4-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 4-bromo-2-methylthiazole (30 mg, 0.13 mmol) and2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (30 mg, 0.17 mmol, Example109(D)). Reaction time: 13 hours. The crude residue was purified byflash chromatography (DCM/MeOH 98:2) to yield 18 mg (66 mmol, 50%) of2-(4-(2-methylthiazol-4-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as ayellow solid.

Rf (DCM/MeOH 98:2)=0.2.

LCMS (RT): 4.01 min; MS (ES+) gave m/z: 269.1.

¹H-NMR (CDCl₃), δ (ppm): 2.69 (s, 3H), 3.27 (t, J=7.6, 2H), 4.97 (t,J=7.6, 2H), 7.20 (s, 1H), 7.40 (dd, J=3.1 and 6.6, 2H), 7.88 (dd, J=3.1and 6.6, 2H).

Example 142 2-(4-(4-o-Tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine

142(A) 1-But-3-ynyl-4-o-tolyl-1H-pyrazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 4-o-tolyl-1H-pyrazole (325 mg, 2.05 mmol). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt9:1) to yield 318 mg (1.51 mmol, 88%) of1-but-3-ynyl-4-o-tolyl-1H-pyrazole.

142(B) 2-(4-(4-o-Tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 50 mg (0.24 mmol) of 1-but-3-ynyl-4-o-tolyl-1H-pyrazole.Reaction time: 13 hours. The crude residue was purified by flashchromatography (DCM/MeOH 98:2) and SCX column (DCM, DCM/MeOH 95:5,DCM/MeOH/NH₄OH 94:5:1) to yield 2 mg (9 mmol, 4%) of 2-(4-(4-O—tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as an orange oil.

LCMS (RT): 4.03 min; MS (ES+) gave m/z: 288.2.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 2.37 (s, 3H), 3.07 (t, J=6.9, 2H), 4.45 (t,J=6.9, 2H), 7.17-7.25 (4H), 7.32-7.36 (2H), 7.59-7.64 (m, 1H), 7.65 (s,1H), 7.68 (s, 1H), 8.54-8.58 (m, 1H).

Example 1432-(Fluoromethyl)-6-(4-(4-o-tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.26 mmol) and1-but-3-ynyl-4-o-tolyl-1H-pyrazole (50 mg, 0.24 mmol, Example 142(A)).Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/MeOH 98:2) to yield 23 mg (72 mmol, 30%) of2-(fluoromethyl)-6-(4-(4-o-tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine asa yellow solid with a purity of 81%.

Rf (DCM/MeOH 98:2)=0.2.

LCMS (RT): 4.43 min; MS (ES+) gave m/z: 320.2.

¹H-NMR (CDCl₃), δ (ppm): 2.37 (s, 3H), 3.07 (t, J=6.9, 2H), 4.44 (t,J=6.9, 2H), 5.40-5.53 (m, 2H), 7.17-7.25 (3H), 7.27-7.32 (m, 1H),7.32-7.43 (2H), 7.65 (s, 1H), 7.68 (s, 1H), 7.68-7.72 (m, 1H).

Example 1442-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (49 mg, 0.26 mmol) and1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole (50 mg, 0.23 mmol, Example140(A)). Reaction time: 13 hours. The crude residue was purified byflash chromatography (DCM/MeOH 98:2) to yield 29 mg (88 mmol, 38%) of2-(fluoromethyl)-6-(4-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridineas a yellow solid.

Rf (DCM/MeOH 98:2)=0.2.

LCMS (RT): 4.29 min; MS (ES+) gave m/z: 324.2.

¹H-NMR (CDCl₃), δ (ppm): 3.05 (t, J=6.9, 2H), 4.42 (t, J=6.9, 2H),5.40-5.53 (m, 2H), 7.03-7.18 (2H), 7.27-7.32 (m, 1H), 7.38-7.45 (3H),7.66-7.71 (m, 1H), 7.73 (s, 1H), 7.77 (s, 1H).

Example 1456-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline145(A) 6-Fluoro-2-methyl-quinoxaline

A solution of 2-oxo-propionaldehyde (0.19 mL, 1.20 mmol) and4-fluoro-benzene-1,2-diamine (150 mg, 1.19 mmol) in water (1.3 mL) wasplaced in a microwave tube and heated for 1 min. at 150 W. Then thereaction mixture was diluted with water and extracted twice with AcOEt.The organic phase was washed with water, brine, dried over MgSO₄,filtered and evaporated. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 4:1) to yield 154 mg (0.95 mmol, 80%)of 6-fluoro-2-methyl-quinoxaline.

LCMS (RT): 3.24 min; MS (ES+) gave m/z: 163.2.

145(B) 6-Fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline

The title compound was prepared in accordance with the general method ofExample 118(A), from 6-fluoro-2-methyl-quinoxaline (100 mg, 0.62 mmol).The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 66 mg (0.24 mmol, 39%) of6-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline as an orange oil.

LCMS (RT): 5.34 min; MS (ES+) gave m/z: 273.3.

145(C) 2-But-3-ynyl-6-fluoro-quinoxaline

The title compound was prepared in accordance with the general method ofExample 108(B), from6-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline (298 mg, 1.09mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 94:6 to 90:10) to yield 90 mg (0.45 mmol, 41%) of2-but-3-ynyl-6-fluoro-quinoxaline as a yellow liquid.

LCMS (RT): 3.89 min; MS (ES+) gave m/z: 201.2.

145(D)6-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline

The title compound was prepared in accordance with the general method ofExample 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (43 mg, 0.22mmol) and 2-but-3-ynyl-6-fluoro-quinoxaline (45 mg, 0.22 mmol).Microwave conditions: 120° C. for 15 minutes. The crude residue waspurified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 45 mg(0.15 mmol, 65%) of6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline as anorange solid with a purity of 85%.

LCMS (RT): 4.21 min; MS (ES+) gave m/z: 310.3.

¹H-NMR (CDCl₃), δ (ppm): 3.05 (t, J=7.3, 2H), 3.36 (t, J=7.3, 2H),5.40-5.53 (m, 2H), 7.26-7.30 (m, 1H), 7.39 (d, J=7.8, 1H), 7.49-7.55 (m,1H), 7.65-7.71 (2H), 8.10 (dd, J=5.8 and 9.2, 1H), 8.82 (s, 1H).

Example 1464-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole146(A) 4-Chloro-1H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 127(A), from 3-chlorobenzene-1,2-diamine (1.00 g, 7.01 mmol) toyield 4-chloro-1H-benzo[d][1,2,3]triazole (975 mg, 6.35 mmol, 91%) as adark solid.

146(B) 2-(But-3-ynyl)-4-chloro-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 4-chloro-1H-benzo[d][1,2,3]triazole (504 mg, 3.28mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 93:7) to yield 60 mg (0.29 mmol, 10%) of2-(but-3-ynyl)-4-chloro-2H-benzo[d][1,2,3]triazole as a yellow solid.

Rf (DCM/MeOH 97:3)=0.3.

146(C)4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (25 mg, 0.16 mmol) and2-(but-3-ynyl)-4-chloro-2H-benzo[d][1,2,3]triazole (30 mg, 0.15 mmol).Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 12 mg (42 μmol, 29%) of4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as anorange solid.

Rf (DCM/MeOH 99:1)=0.05.

LCMS (RT): 3.96 min; MS (ES+) gave m/z: 283.1.

¹H-NMR (CDCl₃), δ (ppm): 3.32 (t, J=7.5, 2H), 5.03 (t, J=7.5, 2H), 7.21(ddd, J=1.1, 4.9 and 7.6, 1H), 7.31-7.38 (2H), 7.41 (d, J=7.3, 1H),7.59-7.65 (m, 1H), 7.80 (dd, J=0.5 and 8.5, 1H), 8.55 (dd, J=0.5 and4.9, 1H).

Example 1474-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (30 mg, 0.16 mmol) and2-(but-3-ynyl)-4-chloro-2H-benzo[d][1,2,3]triazole (30 mg, 0.15 mmol,Example 146(B)). Reaction time: 3 hours. The crude residue was purifiedby flash chromatography (DCM/MeOH 99:1) to yield 16 mg (51 μmol, 35%) of4-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a brown oil.

Rf (DCM/MeOH 99:1)=0.1.

LCMS (RT): 4.44 min; MS (ES+) gave m/z: 315.1, 317.2.

¹H-NMR (CDCl₃), δ (ppm): 3.32 (t, J=7.4, 2H), 5.03 (t, J=7.4, 2H),5.40-5.53 (m, 2H), 7.27-7.35 (2H), 7.40-7.43 (2H), 7.69-7.72 (m, 1H),7.80 (d, J=8.5, 1H).

Example 1486,7-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline148(A) 6,7-Difluoro-2-methyl-quinoxaline

The title compound was prepared in accordance with the general method ofExample 145(A), from 4,5-difluoro-benzene-1,2-diamine (400 mg, 2.77mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 7:3) to yield 333 mg (1.85 mmol, 67%) of6,7-difluoro-2-methyl-quinoxaline.

LCMS (RT): 3.56 min; MS (ES+) gave m/z: 181.1.

148(B) 6,7-Difluoro-2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline

The title compound was prepared in accordance with the general method ofExample 118(A), from 6,7-difluoro-2-methyl-quinoxaline (333 mg, 1.85mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 233 mg (0.85 mmol, 46%) of6,7-difluoro-2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline as an orangeoil.

LCMS (RT): 5.59 min; MS (ES+) gave m/z: 291.3.

148(C) 2-But-3-ynyl-6,7-difluoro-quinoxaline

The title compound was prepared in accordance with the general method ofExample 108(B), from6,7-difluoro-2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline (233 mg, 0.85mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 80 mg (0.37 mmol, 52%) of2-but-3-ynyl-6,7-difluoro-quinoxaline as an orange solid.

LCMS (RT): 4.19 min; MS (ES+) gave m/z: 219.1.

148(D)6,7-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline

The title compound was prepared in accordance with the general method ofExample 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (70 mg, 0.37mmol) and 2-but-3-ynyl-6,7-difluoro-quinoxaline (80 mg, 0.37 mmol).Microwave conditions: 120° C. for 15 minutes. The crude residue waspurified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 16 mg(50 μmol, 14%) of6,7-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxalineas a yellow solid (M.P.: 134.9-138.5° C.).

LCMS (RT): 4.44 min; MS (ES+) gave m/z: 328.1.

¹H-NMR (CDCl₃), δ (ppm): 3.04 (t, J=7.3 2H), 3.35 (t, J=7.3, 2H),5.40-5.53 (m, 2H), 7.25-7.29 (m, 1H), 7.39 (d, J=7.8, 1H), 7.67-7.72 (m,1H), 7.78-7.88 (2H), 8.82 (s, 1H).

Example 1494-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole149(A) 4-Fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole

2-Fluoro-6-nitro-benzaldehyde (180 mg, 1.06 mmol) was added to asolution of 4-trimethylsilanyl-but-3-ynylamine (200 mg, 1.40 mmol) intoluene (2 mL) and the reaction mixture was stirred under reflux for 30min in a Dean-Stark. After evaporation of the solvent, the crude productwas dissolved in triethylphosphite (1 mL) and the reaction mixture wasstirred at 80° C. for 4 hours. After evaporation, the crude product waspurified by by flash chromatography (cyclohexane/AcOEt 92.5:7.5) toyield 4-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (142 mg,0.59 mmol, 52%) as a yellow oil.

Rf (cyclohexane/AcOEt 4:1)=0.3.

LCMS (RT): 5.01 min; MS (ES+) gave m/z: 261.1.

149(B) 2-But-3-ynyl-4-fluoro-2H-indazole

The title compound was prepared in accordance with the general method ofExample 108(B), from4-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (142 mg, 0.59mmol) to yield 104 mg (0.55 mmol) of 2-but-3-ynyl-4-fluoro-2H-indazole.

149(C)4-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (0.12 g, 0.61 mmol)and 2-but-3-ynyl-4-fluoro-2H-indazole (104 mg, 0.55 mmol). Reactiontime: 3 hours. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 3:2) to yield 60 mg (0.20 mmol, 36%) of4-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as abrown solid.

Rf (cyclohexane/AcOEt 1:1)=0.2.

LCMS (RT): 4.04 min; MS (ES+) gave m/z: 298.1.

¹H-NMR (CDCl₃), δ (ppm): 3.18 (t, J=6.9, 2H), 4.68 (t, J=6.9, 2H),5.41-5.54 (m, 2H), 6.71 (dd, J=7.5 and 10.4, 1H), 7.19-7.25 (m, 1H),7.26-7.29 (m, 1H), 7.42 (d, J=7.9, 1H), 7.50 (d, J=8.7, 1H), 7.68-7.73(m, 1H), 8.14 (s, 1H).

Example 150 4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole 150(A)4-Chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole

The title compound was prepared in accordance with the general method ofExample 149(A), from 2-chloro-6-nitro-benzaldehyde (210 mg, 1.13 mmol)and 4-trimethylsilanyl-but-3-ynylamine (210 mg, 1.50 mmol). The crudeproduct was purified by flash chromatography (cyclohexane/AcOEt92.5:7.5) to yield4-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (134 mg, 0.48mmol, 43%) as a yellow oil.

Rf (cyclohexane/AcOEt 4:1)=0.3.

LCMS (RT): 5.21 min; MS (ES+) gave m/z: 277.1.

150(B) 2-But-3-ynyl-4-chloro-2H-indazole

The title compound was prepared in accordance with the general method ofExample 108(B), from4-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (134 mg, 0.48mmol) to yield 99 mg (0.48 mmol) of 2-but-3-ynyl-4-chloro-2H-indazole.

150(C) 4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (42 mg, 0.27 mmol) and2-but-3-ynyl-4-chloro-2H-indazole (50 mg, 0.24 mmol). Reaction time: 8hours. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 1:1) to yield 12 mg (43 mmol, 17%) of4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.

Rf (cyclohexane/AcOEt 1:1)=0.1.

LCMS (RT): 3.91 min; MS (ES+) gave m/z: 282.1.

¹H-NMR (CDCl₃), δ (ppm): 3.18 (t, J=6.9, 2H), 4.69 (t, J=6.9, 2H), 7.08(d, J=7.1, 1H), 7.20-7.25 (2H), 7.33 (d, J=7.8, 1H), 7.60-7.65 (2H),8.16 (s, 1H), 8.57 (d, J=4.3, 1H).

Example 1516-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole151(A) 6-Fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole

The title compound was prepared in accordance with the general method ofExample 149(A), from 4-fluoro-2-nitro-benzaldehyde (180 mg, 1.06 mmol)and 4-trimethylsilanyl-but-3-ynylamine (200 mg, 1.40 mmol). The crudeproduct was purified by by flash chromatography (cyclohexane/AcOEt 4:1)to yield 6-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (310 mg,1.06 mmol).

151(B) 2-But-3-ynyl-6-fluoro-2H-indazole

The title compound was prepared in accordance with the general method ofExample 108(B), from6-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (310 mg, 1.13mmol) to yield 93 mg (0.49 mmol, 43%) of2-but-3-ynyl-6-fluoro-2H-indazole as an orange oil.

151(C)6-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)pyridine (100 mg, 0.54 mmol) and2-but-3-ynyl-6-fluoro-2H-indazole (93 mg, 0.49 mmol). Reaction time: 3hours. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 3:2) to yield 40 mg (0.13 mmol, 27%) of6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as abrown solid.

Rf (cyclohexane/AcOEt 1:1)=0.2.

LCMS (RT): 3.93 min; MS (ES+) gave m/z: 298.1.

¹H-NMR (CDCl₃), δ (ppm): 3.17 (t, J=6.9, 2H), 4.65 (t, J=6.9, 2H),5.40-5.53 (m, 2H), 6.88-6.93 (m, 1H), 7.26 (d, J=7.8, 1H), 7.28-7.32 (m,1H), 7.41 (d, J=7.8, 1H), 7.60-7.65 (m, 1H), 7.67-7.72 (m, 1H), 8.05 (s,1H).

Example 1524-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (51 mg, 0.27 mmol) and2-but-3-ynyl-4-chloro-2H-indazole (50 mg, 0.24 mmol, Example 150(B)).Reaction time: 3 hours. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 3:2) to yield 54 mg (0.17 mmol, 70%)of 4-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazoleas a brown solid.

Rf (cyclohexane/AcOEt 1:1)=0.2.

LCMS (RT): 4.29 min; MS (ES+) gave m/z: 314.1.

¹H-NMR (CDCl₃), δ (ppm): 3.18 (t, J=6.9, 2H), 4.69 (t, J=6.9, 2H),5.41-5.54 (m, 2H), 7.08 (d, J=7.2, 1H), 7.20-7.24 (m, 1H), 7.26-7.30 (m,1H), 7.42 (d, J=7.8, 1H), 7.62 (d, J=8.7, 1H), 7.68-7.72 (m, 1H), 8.15(s, 1H).

Example 1535,6-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole153(A) 5,6-Difluoro-1H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 127(A), from 4,5-difluorobenzene-1,2-diamine (420 mg, 2.91 mmol)to yield 5,6-difluoro-1H-benzo[d][1,2,3]triazole (361 mg, 2.33 mmol,80%) as a dark solid.

153(B) 2-(But-3-ynyl)-5,6-difluoro-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 5,6-difluoro-1H-benzo[d][1,2,3]triazole (389 mg,2.51 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 244 mg (1.18 mmol, 52%) of2-(but-3-ynyl)-5,6-difluoro-2H-benzo[d][1,2,3]triazole as a white solid.

Rf (cyclohexane/AcOEt 4:1)=0.4.

153(C)5,6-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (50 mg, 0.32 mmol) and2-(but-3-ynyl)-5,6-difluoro-2H-benzo[d][1,2,3]triazole (60 mg, 0.29mmol). Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 54 mg (0.19 mol, 66%) of5,6-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a yellow solid (M.P.=131-132° C.).

Rf (DCM/MeOH 99:1)=0.1.

LCMS (RT): 3.85 min; MS (ES+) gave m/z: 285.1.

¹H-NMR (CDCl₃), δ (ppm): 3.28 (t, J=7.4, 2H), 4.95 (t, J=7.4, 2H),7.20-7.23 (m, 1H), 7.33 (d, J=7.8, 1H), 7.58-7.64 (3H), 8.55 (d, J=4.3,1H).

Example 1545,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.32 mmol) and2-(but-3-ynyl)-5,6-difluoro-2H-benzo[d][1,2,3]triazole (60 mg, 0.29mmol, Example 153(B)). Reaction time: 3 hours. The crude residue waspurified by flash chromatography (DCM/MeOH 99:1) to yield 29 mg (92μmol, 32%) of5,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a grey solid (M.P.=104-105° C.).

Rf (DCM/MeOH 99:1)=0.1.

LCMS (RT): 4.28 min; MS (ES+) gave m/z: 317.1.

¹H-NMR (CDCl₃), δ (ppm): 3.28 (t, J=7.4, 2H), 4.95 (t, J=7.4, 2H),5.40-5.53 (m, 2H), 7.29 (d, J=7.8, 1H), 7.41 (d, J=7.8, 1H), 7.57-7.63(2H), 7.68-7.73 (m, 1H).

Example 1557-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole155(A) 7-Fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole

The title compound was prepared in accordance with the general method ofExample 149(A), from 3-fluoro-2-nitro-benzaldehyde (0.2 g, 1.2 mmol) and4-trimethylsilanyl-but-3-ynylamine (0.22 g, 1.5 mmol). The crude productwas purified by flash chromatography (cyclohexane/AcOEt 92.5:7.5) toyield 7-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (117 mg,0.45 mmol) as a yellow oil.

Rf (cyclohexane/AcOEt 4:1)=0.1.

LCMS (RT): 4.83 min; MS (ES+) gave m/z: 261.1.

155(B) 2-But-3-ynyl-7-fluoro-2H-indazole

The title compound was prepared in accordance with the general method ofExample 108(B), from7-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (134 mg, 0.48mmol) to yield 99 mg (0.48 mmol) of 2-but-3-ynyl-7-fluoro-2H-indazole.

155(C)7-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-fluoromethylpyridine (93 mg, 0.49 mmol) and2-but-3-ynyl-7-fluoro-2H-indazole (84 mg, 0.45 mmol). Reaction time: 6hours. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 3:2) to yield 17 mg (57 μmol, 13%) of7-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as abrown solid.

Rf (cyclohexane/AcOEt 1:1)=0.2.

LCMS (RT): 3.83 min; MS (ES+) gave m/z: 298.1.

¹H-NMR (CDCl₃), δ (ppm): 3.17 (t, J=6.9, 2H), 4.66 (t, J=6.9, 2H),5.40-5.54 (m, 2H), 7.07-7.13 (m, 1H), 7.23 (dd, J=1.9 and 9.1, 1H), 7.26(d, J=7.8, 1H), 7.41 (d, J=7.8, 1H), 7.67-7.71 (2H), 8.01 (s, 1H).

Example 1564-Chloro-2-(4-(1-methyl-1H-pyrazol-3-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 108(C), from 3-bromo-1-methyl-1H-pyrazole (70 mg, 0.43 mmol) and2-but-3-ynyl-4-chloro-2H-benzo[d][1,2,3]triazole (89 mg, 0.43 mmol,Example 146(B)). Microwave conditions: The crude residue was purified byflash chromatography (cyclohexane/AcOEt 7:3) to yield 12 mg (42 μmol,10%) of4-chloro-2-(4-(1-methyl-1H-pyrazol-3-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a brown semi-solid.

Rf (cyclohexane/AcOEt 7:3)=0.2.

LCMS (RT): 3.93 min; MS (ES+) gave m/z: 286.1, 288.1.

¹H-NMR (CDCl₃), δ (ppm): 3.27 (t, J=7.6, 2H), 3.88 (s, 3H), 5.00 (t,J=7.6, 2H), 6.31 (d, J=2.2, 1H), 7.28 (d, J=2.2, 1H), 7.32 (dd, J=7.4and 8.5, 1H), 7.41 (dd, J=0.7 and 7.4, 1H), 7.79 (dd, J=0.7 and 8.5,1H).

Example 1576-(4-(4,6-Difluoro-2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-amine

The title compound was prepared in accordance with the general method ofExample 1, from 6-bromo-pyridin-2-ylamine (60 mg, 0.35 mmol) and2-but-3-ynyl-4,6-difluoro-2H-benzo[d][1,2,3]triazole (72 mg, 0.35 mmol,Example 135(B)). Reaction time: 3 hours. The crude residue was purifiedby flash chromatography (DCM/AcOEt 1:1) to yield 65 mg (0.22 mmol, 63%)of6-(4-(4,6-difluoro-2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-amineas a brown solid.

Rf (DCM/AcOEt 1:1)=0.2.

LCMS (RT): 2.63 min; MS (ES+) gave m/z: 300.1.

¹H-NMR (CDCl₃), δ (ppm): 3.27 (t, J=7.5, 2H), 4.45-4.53 (br. s, 2H),4.97 (t, J=7.5, 2H), 6.45 (d, J=8.3, 1H), 6.75 (d, J=7.3, 1H), 6.88-6.95(m, 1H), 7.31 (dd, J=2.0 and 8.3, 1H), 7.37 (dd, J=7.3 and 8.3, 1H).

Example 1582-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-6-methylpyridin-3-amine

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-methyl-pyridin-3-ylamine (80 mg, 0.43 mmol)and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (73 mg, 0.43 mmol, Example109(D)). Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/AcOEt 1:1) to yield 53 mg (0.19 mmol, 45%) of2-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-6-methylpyridin-3-amineas a brown solid.

Rf (DCM/AcOEt 1:1)=0.2.

LCMS (RT): 2.33 min; MS (ES+) gave m/z: 278.1.

¹H-NMR (CDCl₃), δ (ppm): 2.40 (s, 3H), 3.31 (t, J=6.7, 2H), 4.10-4.18(br. s, 2H), 5.02 (t, J=6.7, 2H), 6.87-6.91 (2H), 7.41 (dd, J=3.1 and6.6, 2H), 7.87 (dd, J=3.1 and 6.6, 2H).

Example 159 2-(4-(3-Phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine 159(A)1-But-3-ynyl-3-phenyl-1H-pyrazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 3-phenyl-1H-pyrazole (617 mg, 4.28 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 9:1) toyield 140 mg (0.71 mmol, 25%) of 1-but-3-ynyl-3-phenyl-1H-pyrazole.

159(B) 2-(4-(3-Phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 140 mg (0.71 mmol) of 1-but-3-ynyl-3-phenyl-1H-pyrazole.The crude residue was purified by flash chromatography (DCM/MeOH 99:1)to yield 44 mg (0.16 mmol, 22%) of2-(4-(3-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid.

LCMS (RT): 3.84 min; MS (ES+) gave m/z: 274.1.

Rf (DCM/MeOH 97:3)=0.2.

Example 1604-Nitro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole 160(A)4-Nitro-1H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 127(A), from 3-nitro-benzene-1,2-diamine (2.50 g, 16.3 mmol) toyield 4-nitro-1H-benzo[d][1,2,3]triazole (2.65 g, 16.1 mmol) as a darksolid.

160(B) 2-But-3-ynyl-4-nitro-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 4-nitro-1H-benzo[d][1,2,3]triazole (1.35 g, 8.20mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 95:5 to 90:10) to yield 191 mg (0.88 mmol, 12%) of2-but-3-ynyl-4-nitro-2H-benzo[d][1,2,3]triazole.

Rf (cyclohexane/AcOEt 9:1)=0.1.

160(C) 4-Nitro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (76 mg, 0.48 mmol) and2-but-3-ynyl-4-nitro-2H-benzo[d][1,2,3]triazole (95 mg, 0.44 mmol).Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 40 mg (0.14 mmol, 31%) of4-nitro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as anorange oil.

Rf (DCM/MeOH 99:1)=0.1.

LCMS (RT): 3.47 min; MS (ES+) gave m/z: 294.1.

¹H-NMR (CDCl₃), δ (ppm): 3.12 (t, J=6.9, 2H), 5.37 (t, J=6.9, 2H),7.18-7.22 (m, 1H), 7.26-7.30 (m, 1H), 7.50-7.54 (m, 1H), 7.59-7.64 (m,1H), 8.38 (dd, J=0.9 and 7.8, 1H), 8.45 (dd, J=0.9 and 8.2, 1H),8.49-8.53 (m, 1H).

Example 1612-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-nitro-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (92 mg, 0.48 mmol) and2-but-3-ynyl-4-nitro-2H-benzo[d][1,2,3]triazole (95 mg, 0.44 mmol,Example, 160(B)). Reaction time: 3 hours. The crude residue was purifiedby flash chromatography (DCM/MeOH 99:1) to yield 59 mg (0.18 mol, 42%)of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-nitro-2H-benzo[d][1,2,3]triazoleas an orange oil.

Rf (DCM/MeOH 99:1)=0.1.

LCMS (RT): 3.97 min; MS (ES+) gave m/z: 326.1.

¹H-NMR (CDCl₃), δ (ppm): 3.12 (t, J=6.8, 2H), 5.37 (t, J=6.8, 2H), 5.36(m, 2H), 7.24 (d, J=7.7, 1H), 7.39 (d, J=7.7, 1H), 7.50-7.56 (m, 1H),7.67-7.72 (m, 1H), 8.38 (dd, J=0.9 and 7.8, 1H), 8.46 (dd, J=0.9 and8.2, 1H).

Example 1622-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazol-4-amine

The title compound was prepared in accordance with the general method ofExample 62(A), from4-nitro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole (40mg, 0.14 mmol, Example 160(C)). The crude residue was purified by flashchromatography (DCM/MeOH 98:2) to yield 7 mg (27 mmol, 19%) of2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazol-4-amine as anorange solid.

Rf (DCM/MeOH 98:2)=0.03.

LCMS (RT): 2.62 min; MS (ES+) gave m/z: 264.1.

¹H-NMR (CDCl₃), δ (ppm): 3.22 (t, J=6.7, 2H), 4.00-4.30 (br. s, 2H),5.12 (t, J=6.7, 2H), 6.72 (dd, J=0.5 and 7.3, 1H), 7.12-7.18 (2H),7.20-7.24 (m, 1H), 7.56 (d, J=8.4, 1H), 7.57-7.62 (m, 1H), 8.55 (d,J=4.3, 1H).

Example 1634-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole163(A) 4-Methyl-1H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 127(A), from 3-methyl-benzene-1,2-diamine (1.95 g, 16.0 mmol) toyield 4-methyl-1H-benzo[d][1,2,3]triazole (1.76 g, 13.2 mmol, 83%) as adark solid.

163(B) 2-But-3-ynyl-4-methyl-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 4-methyl-1H-benzo[d][1,2,3]triazole (418 mg, 3.14mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 255 mg (1.38 mmol, 48%) of2-but-3-ynyl-4-methyl-2H-benzo[d][1,2,3]triazole.

Rf (cyclohexane/AcOEt 9:1)=0.2.

163(C)4-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (66 mg, 0.42 mmol) and2-but-3-ynyl-4-methyl-2H-benzo[d][1,2,3]triazole (70 mg, 0.38 mmol).Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 50 mg (0.19 mmol, 50%) of4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as ayellow semi-solid.

Rf (DCM/MeOH 98:2)=0.1.

LCMS (RT): 3.73 min; MS (ES+) gave m/z: 263.1.

¹H-NMR (CDCl₃), δ (ppm): 2.67 (s, 3H), 3.30 (t, J=7.5, 2H), 5.00 (t,J=7.5, 2H), 7.12-7.16 (m, 1H), 7.21 (ddd, J=1.1, 4.9 and 7.6, 1H),7.27-7.31 (m, 1H), 7.33-7.36 (m, 1H), 7.59-7.64 (m, 1H), 7.69 (d, J=8.6,1H), 8.55 (d, J=4.3, 1H).

Example 1642-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-methyl-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (73 mg, 0.39 mmol) and2-but-3-ynyl-4-methyl-2H-benzo[d][1,2,3]triazole (65 mg, 0.35 mmol,163(B)). Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 65 mg (0.22 mmol, 63%) of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-methyl-2H-benzo[d][1,2,3]triazoleas a yellow semi-solid.

Rf (DCM/MeOH 98:2)=0.7.

LCMS (RT): 4.22 min; MS (ES+) gave m/z: 295.1.

¹H-NMR (CDCl₃), δ (ppm): 2.67 (s, 3H), 3.30 (t, J=7.5, 2H), 5.00 (t,J=7.5, 2H), 5.40-5.53 (m, 2H), 7.12-7.16 (m, 1H), 7.27-7.31 (2H), 7.41(d, J=7.8, 1H), 7.67-7.72 (2H).

Example 1652-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-5-methyl-2H-benzo[d][1,2,3]triazole165(A) 5-Methyl-1H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 127(A), from 4-methyl-benzene-1,2-diamine (2.02 g, 16.5 mmol) toyield 5-methyl-1H-benzo[d][1,2,3]triazole (2.05 g, 15.4 mmol, 93%).

165(B) 2-But-3-ynyl-5-methyl-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 5-methyl-1H-benzo[d][1,2,3]triazole (418 mg, 3.14mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 135 mg (0.73 mmol, 26%) of2-but-3-ynyl-5-methyl-2H-benzo[d][1,2,3]triazole.

Rf (cyclohexane/AcOEt 9:1)=0.3.

165(C)2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-5-methyl-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (73 mg, 0.39 mmol) and2-but-3-ynyl-5-methyl-2H-benzo[d][1,2,3]triazole (65 mg, 0.35 mmol).Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 40 mg (0.14 mmol, 39%) of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-5-methyl-2H-benzo[d][1,2,3]triazoleas a yellow solid.

Rf (DCM/MeOH 99:1)=0.1.

LCMS (RT): 4.20 min; MS (ES+) gave m/z: 295.1.

¹H-NMR (CDCl₃), δ (ppm): 2.50 (s, 3H), 3.28 (t, J=7.5, 2H), 4.96 (t,J=7.5, 2H), 5.40-5.53 (m, 2H), 7.23 (dd, J=1.4 and 8.8, 1H), 7.29 (d,J=7.7, 1H), 7.40 (d, J=7.8, 1H), 7.60-7.62 (m, 1H), 7.67-7.72 (m, 1H),7.76 (d, J=8.8, 1H).

Example 1665-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (66 mg, 0.42 mmol) and2-but-3-ynyl-5-methyl-2H-benzo[d][1,2,3]triazole (70 mg, 0.38 mmol,Example 165(B)). Reaction time: 3 hours. The crude residue was purifiedby flash chromatography (DCM/MeOH 99:1) to yield 36 mg (0.14 mmol, 37%)of 5-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole asan orange solid.

Rf (DCM/MeOH 99:1)=0.05.

LCMS (RT): 3.72 min; MS (ES+) gave m/z: 263.1.

¹H-NMR (CDCl₃), δ (ppm): 2.50 (s, 3H), 3.28 (t, J=7.5, 2H), 4.96 (t,J=7.5, 2H), 7.19-7.25 (2H), 7.34 (d, J=7.8, 1H), 7.59-7.64 (2H), 7.76(d, J=8.8, 1H), 8.55 (d, J=4.5, 1H).

Example 1676-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-methylpyridin-2-amine167(A) (6-Bromo-pyridin-2-yl)-methyl-amine

NaH (150 mg, 3.80 mmol, 60%) was added to a solution of6-bromo-pyridin-2-ylamine (300 mg, 1.73 mmol) in DMF at 0° C. followedby iodomethane (3.47 mL, 6.94 mmol). The reaction mixture was stirredfor 1 hour at room temperature and was quenched with water. The aqueousphase was extracted with Et₂O. The organic phase was washed with water,brine, dried over MgSO₄, filtered and evaporated. The crude residue waspurified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 90 mg(0.48 mmol, 28%) of (6-bromo-pyridin-2-yl)-methyl-amine.

LCMS (RT): 3.45 min; MS (ES+) gave m/z: 189.1.

167(B)6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-methylpyridin-2-amine

The title compound was prepared in accordance with the general method ofExample 1, from (6-bromo-pyridin-2-yl)-methyl-amine (105 mg, 0.56 mmol)and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (96 mg, 0.56 mmol, Example109(D)). Reaction time: 3 hours. The crude residue was purified by C₁₈flash chromatography (water to water/acetonitrile 3:2) to yield 22 mg(80 mmol, 14%) of6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-methylpyridin-2-amineas a white solid (M.P.=150-154° C.).

Rf (cyclohexane/AcOEt 7:3)=0.2.

LCMS (RT): 2.47 min; MS (ES+) gave m/z: 278.2.

¹H-NMR (CDCl₃), δ (ppm): 2.89 (d, J=5.4, 3H), 3.26 (t, J=7.5, 2H),4.56-4.67 (br. s, 1H), 4.97 (t, J=7.5, 2H), 6.32 (d, J=8.4, 1H), 6.67(d, J=7.2, 1H), 7.32-7.41 (3H), 7.86 (dd, J=3.0 and 6.6, 2H).

Example 168 2-(4-(3-(4-Fluorophenyl)isoxazol-5-yl)but-1-ynyl)pyridine168(A) 5-Bromomethyl-3-(4-fluoro-phenyl)-isoxazole

The title compound was prepared in accordance with the general method ofExample 119(B), from [3-(4-fluoro-phenyl)-isoxazol-5-yl]-methanol (200mg, 1.03 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 250 mg (0.98 mmol, 94%) of5-bromomethyl-3-(4-fluoro-phenyl)-isoxazole.

168(B) 3-(4-Fluoro-phenyl)-5-(4-trimethylsilanyl-but-3-ynyl)-isoxazole

The title compound was prepared in accordance with the general method ofExample 107(B), from 5-bromomethyl-3-(4-fluoro-phenyl)-isoxazole (100mg, 0.39 mmol) to yield3-(4-fluoro-phenyl)-5-(4-trimethylsilanyl-but-3-ynyl)-isoxazole (110 mg,0.38 mmol, 98%) as a brown oil.

168(C) 5-But-3-ynyl-3-(4-fluoro-phenyl)-isoxazole

The title compound was prepared in accordance with the general method ofExample 108(B), from3-(4-fluoro-phenyl)-5-(4-trimethylsilanyl-but-3-ynyl)-isoxazole (110 mg,0.38 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 55 mg (0.25 mmol, 67%) of5-but-3-ynyl-3-(4-fluoro-phenyl)-isoxazole as a white solid.

168(D) 2-(4-(3-(4-Fluorophenyl) isoxazol-5-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (40 mg, 0.26 mmol) and5-but-3-ynyl-3-(4-fluoro-phenyl)-isoxazole (55 mg, 0.26 mmol). Reactiontime: 2 hours. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1 to 7:3) to yield 19 mg (65 mmol, 25%) of2-(4-(3-(4-fluorophenyl)isoxazol-5-yl)but-1-ynyl)pyridine as a whitesolid (M.P.=83-84° C.).

Rf (cyclohexane/AcOEt 7:3)=0.2.

LCMS (RT): 4.15 min; MS (ES+) gave m/z: 293.2.

¹H-NMR (CDCl₃), δ (ppm): 2.90 (t, J=7.2, 2H), 3.15 (t, J=7.2, 2H), 6.45(s, 1H), 7.09-7.17 (2H), 7.21 (ddd, J=1.2, 5.1 and 7.5, 1H), 7.36 (d,J=8.1, 1H), 7.58-7.65 (m, 1H), 7.74-7.82 (2H), 8.55 (d, J=4.8, 1H).

Example 169N-(6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)acetamide169(A) 6-(4-Benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine

The title compound was prepared in accordance with the general method ofExample 1, from 6-bromo-pyridin-2-ylamine (960 mg, 5.55 mmol) and2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (950 mg, 5.55 mmol, Example109(D)). Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/AcOEt 1:1) to yield 0.45 g (1.71 mmol, 31%) of6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine as a brown solid

Rf (cyclohexane/AcOEt 7:3)=0.2.

LCMS (RT): 2.47 min; MS (ES+) gave m/z: 264.2.

169(B)N-(6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)acetamide

A solution of anhydride acetic (34.9 mg, 0.34 mmol) in DCM was added toa solution of 6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine (90mg, 0.34 mmol) and Et₃N (52 μl, 0.38 mmol) in DCM (2 mL). The reactionmixture was stirred at room temperature for 2 hours and then the solventwas evaporated. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 3:2) to yield 68 mg (0.22 mmol, 65%) ofN-(6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)acetamideas a white solid (M.P.=93-94° C.).

Rf (cyclohexane/AcOEt 3:2)=0.2.

LCMS (RT): 3.62 min; MS (ES+) gave m/z: 306.1.

¹H-NMR (CDCl₃), δ (ppm): 2.15 (s, 3H), 3.27 (t, J=7.5, 2H), 4.97 (t,J=7.5, 2H), 7.06 (dd, J=0.6 and 7.5, 1H), 7.38 (dd, J=3.3 and 6.6, 2H),7.57-7.64 (m, 1H), 7.86 (dd, J=3.0 and 6.6, 2H), 8.13 (d, J=8.4, 1H),8.15-8.20 (br. s, 1H).

Example 1706-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-ethylpyridin-2-amine170(A) (6-Bromo-pyridin-2-yl)-ethyl-amine

The title compound was prepared in accordance with the general method ofExample 167(A), from 6-bromo-pyridin-2-ylamine (500 mg, 2.89 mmol). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt95:5) to yield 280 mg (1.39 mmol, 48%) of(6-bromo-pyridin-2-yl)-ethyl-amine as a colorless liquid.

LCMS (RT): 3.97 min; MS (ES+) gave m/z: 202.1.

170(B)6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-ethylpyridin-2-amine

The title compound was prepared in accordance with the general method ofExample 1, from (6-bromo-pyridin-2-yl)-ethyl-amine (100 mg, 0.50 mmol)and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (0.13 g, 0.75 mmol, Example109(D)). Reaction time: 3 hours. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 7:3) to yield 35 mg (0.12 mmol, 24%)of6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-ethylpyridin-2-amineas a brown solid (M.P.=73-78° C.).

Rf (cyclohexane/AcOEt 7:3)=0.2.

LCMS (RT): 2.77 min; MS (ES+) gave m/z: 292.2.

¹H-NMR (CDCl₃), δ (ppm): 1.23 (t, J=7.2, 3H), 2.88 (s, 1H), 2.95 (s,1H), 3.26 (t, J=7.5, 2H), 4.97 (t, J=7.5, 2H), 6.31 (dd, J=0.6 and 8.4,1H), 6.66 (dd, J=0.6 and 7.5, 1H), 7.33 (d, J=7.5, 1H), 7.38 (dd, J=0.6and 6.6, 2H), 7.87 (dd, J=3.0 and 6.6, 2H).

Example 171 2-(4-(5-(4-Fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine171(A) 1-But-3-ynyl-5-(4-fluoro-phenyl)-1H-pyrazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 5-(4-fluoro-phenyl)-1H-pyrazole (694 mg, 4.28mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 126 mg (0.59 mmol, 21%) of1-but-3-ynyl-5-(4-fluoro-phenyl)-1H-pyrazole.

171(B) 2-(4-(5-(4-Fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 360 mg (1.68 mmol) of1-but-3-ynyl-5-(4-fluoro-phenyl)-1H-pyrazole. The crude residue waspurified by flash chromatography (DCM/MeOH 99:1) to yield 51 mg (0.17mmol, 10%) of2-(4-(5-(4-fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellowsolid.

LCMS (RT): 3.85 min; MS (ES+) gave m/z: 292.0.

Rf (DCM/MeOH 97:3)=0.1.

Example 172 2-(1-Fluoro-4-(pyridin-2-yl)but-3-ynyl)quinoxaline 172(A)1-Quinoxalin-2-yl-but-3-yn-1-ol

To a mixture of magnesium (229 mg, 9.41 mmol), mercuric chloride (13 mg,47 mmol) and few crystals of iodine in Et₂O (1.5 mL), a solution ofpropargyl bromide (0.53 mL, 5.88 mmol) in Et₂O (4.5 mL) was added slowlyin order to maintain a reflux. The reaction mixture was stirred 1 hourand added to a solution of quinoxaline-2-carbaldehyde (500 mg, 3.16mmol) in THF (2 mL). The resulting reaction mixture was stirred at 0° C.for 30 min., at room temperature for 30 min. and was poured ontosaturated NH₄Cl solution. The aqueous phase was extracted with Et₂O. Theaqueous phase was washed with water, brine, dried over MgSO₄, filteredand evaporated. The crude residue was purified by C₁₈ flashchromatography (H₂O/acetonitrile 100:0 to 80:20) to yield 90 mg (0.45mmol, 14%) of 1-quinoxalin-2-yl-but-3-yn-1-ol as a yellow oil.

LCMS (RT): 2.41 min; MS (ES+) gave m/z: 199.1.

172(B) 4-Pyridin-2-yl-1-quinoxalin-2-yl-but-3-yn-1-ol

The title compound was prepared in accordance with the general method ofExample 1, from 2-iodo-pyridine (72 mg, 0.35 mmol) and1-quinoxalin-2-yl-but-3-yn-1-ol (70 mg, 0.35 mmol). Reaction time: 14hours. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 3:2 to DCM/MeOH 9:1) to yield 60 mg (0.22 mmol, 62%)of 4-pyridin-2-yl-1-quinoxalin-2-yl-but-3-yn-1-ol.

LCMS (RT): 2.47 min; MS (ES+) gave m/z: 276.1.

172(C) 2-(1-Fluoro-4-(pyridin-2-yl)but-3-ynyl)quinoxaline

DAST (19 μL, 0.15 mmol) was added dropwise to a solution of4-pyridin-2-yl-1-quinoxalin-2-yl-but-3-yn-1-ol (30 mg, 0.11 mmol) in DCM(1.5 mL) at −78° C. The reaction mixture was stirred for 15 min. at −78°C., quenched by the addition of water at 0° C. and extracted twice withDCM. The organic phase was washed with water, dried over Na₂SO₄,filtered and evaporated. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 1:1) to yield 10 mg (36 μmol, 33%) of2-(1-fluoro-4-(pyridin-2-yl)but-3-ynyl)quinoxaline as an orangesemi-solid with a purity of 70%.

LCMS (RT): 3.55 min; MS (ES+) gave m/z: 278.0.

¹H-NMR (CDCl₃), δ (ppm): 3.20-3.56 (2H), 5.90-6.11 (m, 1H), 7.17-7.22(m, 1H), 7.31-7.35 (m, 1H), 7.56-7.63 (m, 1H), 7.77-7.83 (2H), 8.07-8.18(2H), 8.50-8.55 (m, 1H), 9.15 (s, 1H).

Example 173N-(6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)methylsulfonamide173(A)N-Methylsulfonyl-N-[6-(4-benzo[d][1,2,3]triazol-2-yl-but-1-ynyl)-pyridin-2-yl]-methylsulfonamide

A solution of methanesulfonyl chloride (98 mg, 0.85 mmol) in DCM wasadded to a solution of6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine (100 mg, 0.38 mmol,Example 169(A)) and Et₃N (0.12 mL, 0.85 mmol) in DCM (2 mL). Thereaction mixture was stirred at room temperature for 2 hours and thenthe solvent was evaporated. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 3:2) to yield 140 mg (0.33 mmol, 88%)ofN-methylsulfonyl-N-[6-(4-benzo[d][1,2,3]triazol-2-yl-but-1-ynyl)-pyridin-2-yl]-methylsulfonamideas a white solid.

LCMS (RT): 4.00 min; MS (ES+) gave m/z: 420.1.

173(B)N-(6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)methylsulfonamide

A solution of NaOH (130 mg, 3.30 mmol) in water (3M) was added to asolution ofN-methylsulfonyl-N-[6-(4-benzo[d][1,2,3]triazol-2-yl-but-1-ynyl)-pyridin-2-yl]-methylsulfonamide(140 mg, 0.33 mmol) in THF (3 mL). The reaction mixture was stirred 4hours at room temperature. The aqueous phase was extracted with DCM. Theorganic phase was washed with water, dried over Na₂SO₄, filtered andevaporated. Diisopropyl ether was added and the crude product wastriturated, filtered and dried to yield 70 mg (0.20 mmol, 62%) ofN-(6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)methylsulfonamideas a white powder (M.P.=65-68° C.).

LCMS (RT): 3.75 min; MS (ES+) gave m/z: 342.1.

Example 174 2-(4-(3-Methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridineand 2-(4-(5-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine 174(A)1-But-3-ynyl-5-methyl-4-phenyl-1H-pyrazole and1-but-3-ynyl-3-methyl-4-phenyl-1H-pyrazole

The title compounds were prepared in accordance with the general methodof Example 109(D), from 5-methyl-4-phenyl-1H-pyrazole (515 mg, 3.25mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 255 mg (1.21 mmol, 42%) of1-but-3-ynyl-5-methyl-4-phenyl-1H-pyrazole and1-but-3-ynyl-3-methyl-4-phenyl-1H-pyrazole.

174(B) 2-(4-(3-Methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine and2-(4-(5-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine

The title compounds were prepared in accordance with the general methodof Example 1, from 255 mg (1.21 mmol) of1-but-3-ynyl-5-methyl-4-phenyl-1H-pyrazole and1-but-3-ynyl-3-methyl-4-phenyl-1H-pyrazole. The crude residue waspurified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 33 mg(0.11 mol, 10%) of2-(4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine and2-(4-(5-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a orangeoil.

LCMS (RT): 3.80 min; MS (ES+) gave m/z: 288.0.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 2.41 (s, 3H), 2.46 (s, 3H), 3.01 (t, J=6.9,2H), 3.02 (t, J=6.9, 2H), 4.34 (t, J=6.9, 2H), 4.38 (t, 6.9, 2H),7.20-7.25 (2H), 7.28-7.40 (12H), 7.57-7.63 (4H), 8.55-8.57 (2H).

Example 175N-(6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)formamide

A solution of anhydride acetic (0.75 mL) and formic acid (0.32 mL) washeated at 60° C. for 3 hours. The reaction mixture was cooled to roomtemperature, 6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine (70mg, 0.27 mmol, 169(A)) was added over 15 min. and the reaction mixturewas stirred at room temperature for 1 day. After evaporation of thesolvent, the crude residue was triturated with diisopropyl ether,filtered and dried to yield 25 mg (86 μmol, 32%) ofN-(6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)formamideas a brown solid.

LCMS (RT): 3.38 min; MS (ES+) gave m/z: 292.1.

¹H-NMR (CDCl₃), δ (ppm): 3.31 (t, J=7.2, 2H), 5.00 (t, J=7.2, 2H),7.31-7.44 (3H), 7.49 (dd, J=0.6 and 8.1, 1H), 7.72-7.79 (m, 1H),7.84-7.91 (2H), 9.34 (s, 1H).

Example 1764-Chloro-2-(4-(1,2-dimethyl-1H-imidazol-4-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 108(C), from 4-bromo-1,2-dimethyl-1H-imidazole (85 mg, 0.49mmol) and 2-but-3-ynyl-4-chloro-2H-benzo[d][1,2,3]triazole (100 mg, 0.49mmol, Example 146(B)). Microwave conditions: 100° C. for 15 min. Thecrude residue was purified by C₁₈ flash chromatography to yield 8.0 mg(27 μmol, 5%) of4-chloro-2-(4-(1,2-dimethyl-1H-imidazol-4-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a brown semi-solid.

Rf (cyclohexane/AcOEt 7:3)=0.2.

LCMS (RT): 2.55 min; MS (ES+) gave m/z: 300.2, 302.1.

¹H-NMR (CDCl₃), δ (ppm): 2.33 (s, 3H), 3.24 (t, J=7.5, 2H), 3.52 (s,3H), 4.96 (t, J=7.5, 2H), 6.90 (s, 1H), 7.27-7.34 (m, 1H), 7.39 (dd,J=0.9 and 7.2, 1H), 7.77 (dd, J=0.9 and 8.4, 1H).

Example 1774,5-Dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole177(A) 4,5-Dimethyl-1H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 127(A), from 3,4-dimethyl-benzene-1,2-diamine (500 mg, 3.67mmol) to yield 4,5-dimethyl-1H-benzo[d][1,2,3]triazole (520 mg, 3.53mmol, 95%) as a brown solid.

177(B) 2-But-3-ynyl-4,5-dimethyl-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 4,5-dimethyl-1H-benzo[d][1,2,3]triazole (520 mg,3.53 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 131 mg (0.66 mmol, 20%) of2-but-3-ynyl-4,5-dimethyl-2H-benzo[d][1,2,3]triazole.

Rf (cyclohexane/AcOEt 4:1)=0.5.

177(C)4,5-Dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (65 mg, 0.41 mmol) and2-but-3-ynyl-4,5-dimethyl-2H-benzo[d][1,2,3]triazole (75 mg, 0.38 mmol).Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/MeOH 98:2) to yield 65 mg (0.23 mmol, 63%) of4,5-dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas an orange oil.

Rf (DCM/MeOH 98:2)=0.1.

LCMS (RT): 4.05 min; MS (ES+) gave m/z: 277.1.

¹H-NMR (CDCl₃), δ (ppm): 2.39 (s, 3H), 2.57 (s, 3H), 3.27 (t, J=7.5,2H), 4.96 (t, J=7.5, 2H), 7.19-7.25 (2H), 7.34 (d, J=8.1, 1H), 7.58 (d,J=8.7, 1H), 7.58-7.63 (m, 1H), 8.55 (d, J=5.1, 1H).

Example 1782-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-4,5-dimethyl-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (79 mg, 0.41 mmol) and2-but-3-ynyl-4,5-dimethyl-2H-benzo[d][1,2,3]triazole (75 mg, 0.38 mmol,177(B)). Reaction time: 3 hours. The crude residue was purified by flashchromatography (DCM/MeOH 98:2) to yield 46 mg (0.15 mmol, 40%) of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-4,5-dimethyl-2H-benzo[d][1,2,3]triazoleas an orange oil.

Rf (DCM/MeOH 98:2)=0.1.

LCMS (RT): 4.48 min; MS (ES+) gave m/z: 309.1.

¹H-NMR (CDCl₃), δ (ppm): 2.40 (s, 3H), 2.58 (s, 3H), 3.27 (t, J=7.5,2H), 4.95 (t, J=7.5, 2H), 5.40-5.55 (m, 2H), 7.20 (d, J=8.7, 1H), 7.29(d, J=7.8, 1H), 7.40 (d, J=8.0, 1H), 7.58 (d, J=8.7, 1H), 7.66-7.72 (m,1H).

Example 1792-(4-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine179(A) 4-(4-Fluoro-phenyl)-1H-[1,2,3]triazole

Sodium azide (4.28 g, 65.8 mmol) was added to a solution(E)-1-fluoro-4-(2-nitro-vinyl)-benzene (1.00 g, 5.98 mmol) in DMSO (50mL), the solution was stirred at room temperature for 14 hours and thereaction mixture was poured onto water. The aqueous phase was extractedwith AcOEt. The organic phase was washed with saturated solution ofNaHCO₃, brine, dried over MgSO₄, filtered and evaporated to yield 300 mg(1.84 mmol, 31%) of 4-(4-fluoro-phenyl)-1H-[1,2,3]triazole.

179(B) 1-But-3-ynyl-4-(4-fluoro-phenyl)-1H-[1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 109(D), from 4-(4-fluoro-phenyl)-1H-[1,2,3]triazole (306 mg,1.87 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 95:5 to 90:10) to yield 80 mg (0.37 mmol, 21%) of1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-[1,2,3]triazole.

Rf (cyclohexane/AcOEt 4:1)=0.1.

179(C)2-(4-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (65 mg, 0.41 mmol) and1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-[1,2,3]triazole (80 mg, 0.37 mmol).Reaction time: 13 hours. The crude residue was purified by flashchromatography (DCM/MeOH 98.5:1.5) to yield 28 mg (96 μmol, 26%) of2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as abrown solid (M.P.=120-122° C.).

Rf (DCM/MeOH 98.5:1.5)=0.1.

LCMS (RT): 3.45 min; MS (ES+) gave m/z: 293.1.

¹H-NMR (CDCl₃), δ (ppm): 3.10 (t, J=6.7, 2H), 4.68 (t, J=6.7, 2H),7.07-7.14 (m, 2H), 7.22-7.26 (m, 1H), 7.34 (d, J=7.8, 1H), 7.61-7.65 (m,1H), 7.81 (dd, J=5.1 and 8.7, 2H), 7.97 (s, 1H), 8.58 (d, J=4.5, 1H).

Example 1802-(4-(6-Chloropyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 108(C), from 2,6-dichloropyridine (150 mg, 1.01 mmol) and2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (0.17 g, 1.00 mmol, Example109(D)). Microwave conditions: 120° C. for 15 min. The crude residue waspurified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 15 mg(53 mmol, 5%) of2-(4-(6-chloropyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as ayellow solid.

Rf (cyclohexane/AcOEt 4:1)=0.2.

LCMS (RT): 4.32 min; MS (ES+) gave m/z: 283.1, 285.1.

Example 1812-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-3-methylquinoxaline181(A) 2-Methyl-3-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline

The title compound was prepared in accordance with the general method ofExample 118(A), from 2,3-dimethyl-quinoxaline (300 mg, 1.90 mmol). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt9:1) to yield 200 mg (0.74 mmol, 39%) of2-methyl-3-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline as an orange oil.

LCMS (RT): 5.12 min; MS (ES+) gave m/z: 269.1.

181(B) 2-But-3-ynyl-3-methyl-quinoxaline

The title compound was prepared in accordance with the general method ofExample 108(B), from2-methyl-3-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline (143 mg, 0.53mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 94:6 to 90:10) to yield 20 mg (0.10 mmol, 19%) of2-but-3-ynyl-3-methyl-quinoxaline as an orange liquid.

LCMS (RT): 3.59 min; MS (ES+) gave m/z: 197.1.

181(C)2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-3-methylquinoxaline

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)-pyridine (24 mg, 0.13 mmol) and2-but-3-ynyl-3-methyl-quinoxaline (25 mg, 0.13 mmol). Reaction time: 14hours. The crude residue was purified by preparative chromatographyplate (Et₂O/pentane 7:3) to yield 6.4 mg (21 μmol, 13%) of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-3-methylquinoxaline as ayellow solid.

¹H-NMR (CDCl₃), δ (ppm): 2.73 (s, 3H), 3.04 (t, J=7.1, 2H), 3.29 (t,J=7.1, 2H), 5.30-5.49 (m, 2H), 7.23 (d, J=7.7, 1H), 7.31 (d, J=7.8, 1H),7.59-7.65 (3H), 7.91-7.98 (2H).

Example 1822-(4-(6-(1-Fluoroethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole182(A) 1-[6-(4-Benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yl]-ethanone

The title compound was prepared in accordance with the general method ofExample 1, from 1-(6-bromo-pyridin-2-yl)-ethanone (500 mg, 2.66 mmol)and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (455 mg, 2.66 mmol, Example109(D)). Reaction time: 3 hours. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 4:1) to yield 380 mg (1.36 mmol, 51%)of 1-[6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yl]-ethanone as awhite solid.

Rf (cyclohexane/AcOEt 7:3)=0.3.

LCMS (RT): 4.14 min; MS (ES+) gave m/z: 279.0.

182(B) 1-[6-(4-Benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yl]-ethanol

NaBH₄ (99 mg, 1.6 mmol) was added to a solution of146-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yThethanone (380 mg, 1.31mmol) in MeOH (5 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 30 min., quenched by the addition of water at 0° C. andextracted twice with DCM. The organic phase was washed with water, driedover Na₂SO₄, filtered and evaporated. The crude residue was purified byflash chromatography (cyclohexane/AcOEt 3:2) to yield 202 mg (0.69 mmol,53%) of 146-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yThethanol as acolorless oil.

182(C)2-(4-(6-(1-Fluoroethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 172(C) from1-[6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yl]-ethanol (100 mg,0.34 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 50 mg (0.17 mmol, 50%) of2-(4-(6-(1-fluoroethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazoleas a colorless oil.

Rf (cyclohexane/AcOEt 4:1)=0.2.

LCMS (RT): 4.28 min; MS (ES+) gave m/z: 295.2.

¹H-NMR (CDCl₃), δ (ppm): 1.65 (dd, J=6.3 and 24.6, 3H), 3.30 (t, J=7.5,2H), 4.99 (t, J=7.5, 2H), 5.53-5.76 (m, 1H), 7.24-7.28 (m, 1H),7.36-7.43 (3H), 7.63-7.70 (m, 1H), 7.84-7.91 (2H).

Example 183 2-(4-(Pyridin-2-yl)but-3-ynyl)isoquinolin-1(2H)-one 183(A)2-But-3-ynyl-2H-isoquinolin-1-one

The title compound was prepared in accordance with the general method ofExample 109(D), from 2H-isoquinolin-1-one (200 mg, 1.38 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 99:1) to yield125 mg (0.63 mmol, 46%) of 2-but-3-ynyl-2H-isoquinolin-1-one.

Rf (DCM/MeOH 99:1)=0.2.

LCMS (RT): 3.47 min; MS (ES+) gave m/z: 198.1.

183(B) 2-(4-(Pyridin-2-yl)but-3-ynyl)isoquinolin-1(2H)-one

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromopyridine (100 mg, 0.63 mmol) and2-but-3-ynyl-2H-isoquinolin-1-one (120 mg, 0.63 mmol). Reaction time: 3hours. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 17 mg (62 μmol, 10%) of2-(4-(pyridin-2-yl)but-3-ynyl)isoquinolin-1(2H)-one as a white solid(M.P.=85-90° C.).

LCMS (RT): 3.25 min; MS (ES+) gave m/z: 275.2.

¹H-NMR (CDCl₃), δ (ppm): 2.98 (t, J=6.6, 2H), 4.25 (t, J=6.6, 2H), 6.50(d, J=7.5, 1H), 7.17-7.23 (m, 1H), 7.32 (d, J=7.8, 1H), 7.42-7.55 (3H),7.57-7.71 (2H), 8.44 (d, J=8.1, 1H), 8.55 (d, J=4.8, 1H).

Example 1842,6-Dimethoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

2,6-Dimethoxy-benzoyl chloride (81 mg, 0.41 mmol) was added to asolution of methyl-(4-pyridin-2-yl-but-3-ynyl)-amine (50 mg, 0.31 mmol)and DIEA (69 μL, 0.41 mmol) in chloroform (2 mL) at 0° C. The reactionmixture was stirred at 0° C. for 10 min., at room temperature for 14hours, quenched by the addition of water and extracted twice withchloroform. The organic phase was washed with saturated solution ofNaHCO₃, brine, dried over MgSO₄, filtered and evaporated. The cruderesidue was purified by flash chromatography (DCM/MeOH 95:5) to yield2,6-dimethoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide (12 mg,37 μmol, 12%).

LCMS (RT): 3.00 min; MS (ES+) gave m/z: 325.1.

¹H-NMR (CDCl₃), δ (ppm): 3.02 (t, J=7.5, 2H), 3.34 (t, J=7.5, 2H),7.17-7.21 (m, 1H), 7.33 (d, J=7.8, 1H), 7.43 (d, J=8.4, 1H), 7.49-7.54(m, 1H), 7.58-7.63 (m, 1H), 7.69-7.74 (m, 1H), 7.81 (d, J=8.1, 1H), 8.08(d, J=8.4, 1H), 8.12 (d, J=8.4, 1H), 8.55

Example 1852,6-Difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 186, from 2,6-difluoro-benzoyl chloride (51 μL, 0.41 mmol). Thecrude residue was purified by flash chromatography (DCM/MeOH 95:5) toyield 38 mg (13 μmol, 40%) of2,6-difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide.

LCMS (RT): 3.22 min; MS (ES+) gave m/z: 301.1.

Example 186 N-(2-Fluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide 186(A)N-(2-Fluorophenyl)pent-4-ynamide

The title compound was prepared in accordance with the general method ofExample 34(A), from 2-fluoro-aniline (566 mg, 5.10 mmol). The cruderesidue was purified by flash chromatography (DCM) to yield 710 mg (3.71mmol, 73%) of N-(2-fluorophenyl)pent-4-ynamide as a white solid.

LCMS (RT): 3.33 min; MS (ES+) gave m/z: 192.1.

Rf (DCM)=0.2.

186(B) (2-Fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester

The title compound was prepared in accordance with the general method ofExample 34(B), from N-(2-fluorophenyl)pent-4-ynamide (700 mg, 3.66mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 1.08 g (3.71 mmol, 100%) of(2-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester as acolourless oil.

LCMS (RT): 4.75 min; MS (ES+) gave m/z: 192.1.

Rf (cyclohexane/AcOEt 9:1)=0.3.

186(C) (2-Fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acidtert-butyl ester

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (136 mg, 0.86 mmol) and(2-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (250 mg,0.86 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 240 mg (0.65 mmol, 76%) of(2-fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid-tert-butylester as a white solid.

LCMS (RT): 4.60 min; MS (ES+) gave m/z: 369.1.

Rf (cyclohexane/AcOEt 4:1)=0.2.

186(D) N-(2-Fluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide

The title compound was prepared in accordance with the general method ofExample 34(D), from(2-fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid-tert-butylester (240 mg, 0.65 mmol). After the work-up, the crude residue waswashed with diisopropyl ether/pentane 1:1 to yield 120 mg (0.45 mmol,69%) of N-(2-fluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide as a beigepowder (M.P.=82-84° C.).

LCMS (RT): 3.10 min; MS (ES+) gave m/z: 269.1.

¹H-NMR (CDCl₃), δ (ppm): 2.75 (t, J=6.9, 2H), 2.87 (t, J=6.9, 2H),7.00-7.16 (3H), 7.20 (ddd, J=1.2, 5.1 and 7.8, 1H), 7.37 (d, J=7.8, 1H),7.57-7.66 (m, 1H), 7.67-7.77 (m, 1H), 8.24-8.35 (m, 1H), 8.53 (d, J=4.8,1H).

Example 187 N-(3-Fluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide 187(A)N-(3-Fluorophenyl)pent-4-ynamide

The title compound was prepared in accordance with the general method ofExample 34(A), from 3-fluoro-aniline (566 mg, 5.10 mmol). The cruderesidue was purified by flash chromatography (DCM) to yield 660 mg (3.45mmol, 68%) of N-(3-fluorophenyl)pent-4-ynamide as a white solid.

LCMS (RT): 3.53 min; MS (ES+) gave m/z: 192.1.

Rf (DCM)=0.2.

187(B) (3-Fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester

The title compound was prepared in accordance with the general method ofExample 34(B), from N-(3-fluorophenyl)pent-4-ynamide (660 mg, 3.45mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 1.00 g (3.43 mmol) of(3-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester as acolourless oil.

LCMS (RT): 4.68 min; MS (ES+) gave m/z: 191.1.

Rf (Cyclohexane/AcOEt 9:1)=0.3.

187(C) (3-Fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acidtert-butyl ester

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (137 mg, 0.86 mmol) and(3-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (250 mg,0.86 mmol). Reaction time: 3 hours. The crude residue was purified byflash chromatography (cyclohexane/AcOEt 4:1) to yield 190 mg (0.52 mmol,60%) of (3-fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acidtert-butyl ester as a white solid.

LCMS (RT): 4.48 min; MS (ES+) gave m/z: 369.1.

Rf (cyclohexane/AcOEt 4:1)=0.2.

187(D) N-(3-Fluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide

The title compound was prepared in accordance with the general method ofExample 34(D), from(3-fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid tert-butylester (190 mg, 0.52 mmol). After the work-up, the crude residue waswashed with pentane to yield 125 mg (0.47 mmol, 90%) ofN-(3-fluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide as a beige powder(M.P.=110-114° C.).

LCMS (RT): 3.40 min; MS (ES+) gave m/z: 269.1.

Example 188 N-(4-Fluoro-2-methyl-phenyl)-5-(pyridin-2-yl)pent-4-ynamide188(A) N-(4-Fluoro-2-methyl-phenyl)pent-4-ynamide

The title compound was prepared in accordance with the general method ofExample 34(A), from 4-fluoro-2-methyl-phenylamine (638 mg, 5.10 mmol).The crude residue was purified by flash chromatography (DCM) to yield510 mg (2.49 mmol, 49%) of N-(4-fluoro-2-methyl-phenyl)pent-4-ynamide asa white solid.

Rf (DCM)=0.2.

188(B) (4-Fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamic acid tert-butylester

The title compound was prepared in accordance with the general method ofExample 34(B), from N-(4-fluoro-2-methyl-phenyl)pent-4-ynamide (500 mg,2.63 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 790 mg (2.59 mmol) of(4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl esteras a colourless oil.

Rf (Cyclohexane/AcOEt 9:1)=0.3.

188(C) (4-Fluoro-2-methyl-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamicacid tert-butyl ester

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-pyridine (129 mg, 0.82 mmol) and(4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester(250 mg, 0.82 mmol). Reaction time: 3 hours. The crude residue waspurified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 190 mg(0.50 mmol, 61%) of(4-fluoro-2-methyl-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acidtert-butyl ester as a white solid.

LCMS (RT): 4.78 min; MS (ES+) gave m/z: 382.4.

188(D) N-(4-Fluoro-2-methyl-phenyl)-5-(pyridin-2-yl)pent-4-ynamide

The title compound was prepared in accordance with the general method ofExample 34(D), from(4-fluoro-2-methyl-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acidtert-butyl ester (220 mg, 0.58 mmol). After the work-up, the cruderesidue was washed with pentane to yield 85 mg (0.30 mmol, 52%) ofN-(4-fluoro-2-methyl-phenyl)-5-(pyridin-2-yl)pent-4-ynamide as a beigepowder (M.P.=110-114° C.).

LCMS (RT): 3.13 min; MS (ES+) gave m/z: 283.1.

Example 1892,6-Dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide189(A) 2-(4-(Trimethylsilyl)but-3-ynyl)isoindoline-1,3-dione

The title compound was prepared in accordance with the general method ofExample 109(D), from 4-(trimethylsilyl)but-3-yn-1-ol (3.20 g, 22.5 mmol)and phthalimide (3.50 g, 23.8 mmol). The crude residue was purified byflash chromatography (cyclohexane/AcOEt 9:1) to yield 3.1 g (11 mmol,51%) of 2-(4-(trimethylsilyl)but-3-ynyl)isoindoline-1,3-dione as a whitesolid.

189(B) 2-(But-3-ynyl)isoindoline-1,3-dione

The title compound was prepared in accordance with the general method ofExample 108(B), from2-(4-(trimethylsilyl)but-3-ynyl)isoindoline-1,3-dione (3.10 g, 11.4mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 985 mg (4.94 mmol, 43%) of2-(but-3-ynyl)isoindoline-1,3-dione as a white solid.

189(C)2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)pyridine (336 mg, 1.77 mmol,Example 190(E)) and 2-(but-3-ynyl)isoindoline-1,3-dione (320 mg, 1.61mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 75:25) to yield 320 mg (1.04 mmol, 65%) of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as awhite solid.

LCMS (RT): 3.97 min; MS (ES+) gave m/z: 309.1.

189(D) 4-(6-(Fluoromethyl)pyridin-2-yl)but-3-yn-1-amine

Hydrazine hydrate (1.0 mL, 5.2 mmol) was added to a solution of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione (320mg, 1.04 mmol) in EtOH (3 mL) and the reaction mixture was stirred for 4hours at 50° C. The mixture was cooled down, DCM was added and theaqueous phase was extracted. The organic phase was washed with saturatedsolution of NaHCO₃, dried over Na₂SO₄, filtered and concentrated toyield 117 mg (0.66 mmol, 63%) of4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine as a white solid.

189(E)2,6-Dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 184, from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine (39mg, 0.22 mmol) and 2,6-dichlorobenzoyl chloride (60 mg, 0.28 mmol). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt7:3) to yield 21 mg (0.06 mmol, 27%) of2,6-dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide asa yellow oil.

LCMS (RT): 3.72 min; MS (ES+) gave m/z: 351.0, 3.53.0.

Example 1902-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole190(A) (1-Methyl-1H-benzo[d]imidazol-2-yl)methanol

A solution of 1-methyl-1H-benzo[d]imidazole-2-carbaldehyde (473 mg, 2.95mmol) in MeOH (0.3 M, 10 mL) was cooled at 0° C. before the addition insmall portions of NaBH₄ (559 mg, 14.80 mmol). After 90 min at 0° C., thereaction mixture was quenched with saturated NaHCO₃, extracted twicewith Et₂O. The combined organic layers were washed with saturated brineand dried over MgSO₄. The solvent was removed under reduced pressure toafford 418 mg of 1-methyl-1H-benzo[d]imidazol-2-yl)methanol (Yield: 87%)as a white solid. The crude product was used in the next step withoutany further purification.

Rf (DCM/MeOH:95/5)=0.19

190(B) 2-(Chloromethyl)-1-methyl-1H-benzo[d]imidazole

1-Methyl-1H-benzo[d]imidazol-2-yl)methanol (418 mg, 2.58 mmol) waspartially dissolved in DCM (2 mL). At room temperature thionyl chloride(12.90 mmol, 0.935 mL) was added in one portion to the resultingsuspension. The reaction mixture was stirred at room temperature for 90min. The solvent was removed under reduced pressure to give a yellowsolid. The solid was poured into saturated NaHCO₃ and extracted twicewith Et₂O. The combined organic layers were washed with saturated brineand dried over MgSO₄. The solvent was removed under reduced pressure andthe crude product was purified by Flash chromatography (prepacked 25 gsilicagel column, DCM/MeOH from 100/0 to 97/3 as eluent) to afford 380mg of 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole (Yield: 81%) as awhite-pink solid.

Rf (DCM/MeOH:95/5)=0.50

190(C) 1-Methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 67(D), from trimethyl(prop-1-ynyl)silane (283 mg, 2.52 mmol) and2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole (380 mg, 2.10 mmol). Thecrude product was purified over prepacked 25 g silicagel column(DCM/MeOH from 100/0 to 98/2 as eluent) to afford 317 mg of1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (Yield:59%) as red solid.

Rf (DCM/MeOH:98/2)=0.37

LCMS (RT): 3.25 min; MS (ES+) gave m/z: 257.2

190(D) 2-(But-3-ynyl)-1-methyl-1H-benzo[d]imidazole

According to the protocol described in Example 38(D), the conversion of1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (317 mg,1.23 mmol) afforded 146 mg of2-(but-3-ynyl)-1-methyl-1H-benzo[d]imidazole (Yield: 64%) asyellow-orange solid. Purification over silicagel chromatography(prepacked 25 g silicagel column, DCM/MeOH: 99/1 as eluent).

LCMS (RT): 0.65-1.93 min; MS (ES+) gave m/z: 185

Rf (DCM/MeOH: 95/5)=0.29

190(E) 2-Bromo-6-(fluoromethyl)pyridine

A solution of (6-bromopyridin-2-yl)methanol (5 g, 27 mmol) in dry DCM(60 mL) was added dropwise at −78° C. to a cooled solution of DAST (13g, 80 mmol) in dry DCM (50 mL). The reaction mixture was stirred 1 h at−78° C. then 1 h at room temperature. To complete the reaction, anadditional 5 mL of DAST were slowly added at −60° C. and the reactionmixture was kept overnight at room temperature. The reaction wasquenched with water and the organic layer extracted with DCM, dried overMgSO₄ and evaporated. Purification over silicagel chromatography(prepacked 85 g silicagel column, Cyclohexane/AcOEt:90/10 as eluent) toafford 4.50 g of 2-bromo-6-(fluoromethyl)pyridine (Yield: 89%) as paleyellow oil which crystallized at 0° C.

LCMS (RT): 3.42 min; MS (ES+) gave m/z: 191,192

Rf (Cyclohexane/AcOEt:90/10)=0.4

¹NMR(CDCl₃), δ (ppm): 7.60-7.50 (m, 1H), 7.40-7.30 (m, 2H), 5.55-5.25(d, 2H)

190(F)2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole

In a dry microwave tube were placed in suspension CuI (7.55 mg, 0.039mmol) and triethylamine (1.45 mL, 10.30 mmol). Then under nitrogenatmosphere, were added the 2-bromo-6-(fluoromethyl)pyridine (151 mg,0.79 mmol), PdCl₂(PPh₃)₂ (27.80 mg, 0.039 mmol) and triphenyl phosphinepolymerbound (41.6 mg, 0.158 mmol). The suspension was stirred at roomtemperature for few minutes, finally the2-(but-3-ynyl)-1-methyl-1H-benzo[d]imidazole (146 mg, 0.792 mmol) in 1.1mL of DMF was added, and the reaction mixture was stirred at roomtemperature for 30 min.

The reaction mixture was stirred and heated under micro wave irradiationfor 15 min at 120° C. After filtering to remove triphenyl phosphinepolymerbound, the triethylamine was concentrated under reduce pressureand the residue was dissolved in DCM. The organic layer was washed withsaturated NaHCO₃, H₂O and saturated brine. The organic layer was driedover Na₂SO₄, filtered and concentrated.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, DCM/MeOH: from 100/0 to 98.5/1.5 as eluent) to afford 127 mg of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazoleas a yellow solid (Mp=95.3-96.3° C.).

Rf (DCM/MeOH:95/5)=0.13

LCMS (RT): 2.41 min; MS (ES+) gave m/z: 294

¹H-NMR (CDCl₃), δ (ppm): 7.80-7.65 (m, 2H), 7.45-7.20 (m, 5H), 5.60-5.38(d, 2H), 3.80 (s, 3H), 3.30-3.20 (m, 2H), 3.15-3.05 (m, 2H).

Example 1917-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole191(A) 2-Chloro-N-methyl-6-nitrobenzenamine

2-Fluoro-3-chloronitrobenzene (3.0 g, 17 mmol) was dissolved in EtOH (6mL) and Methylamine 40% in Water (6 mL) was added dropwise at 0° C. andmixture was warmed up to RT overnight. Mixture went to a dark orangeprecipitate within 10 min. The solid was isolated by filtration, rinsedwith water (2*10 mL) and dried in a desiccators under vacuum to afford 3g of 2-chloro-N-methyl-6-nitrobenzenamine (Yield: 90%) as an orangecrystalline solid.

Rf (Cyclohexane/EtOAc:80/20)=0.52

LCMS (RT): 4.29 min

191(B) 6-Chloro-N′-methylbenzene-1,2-diamine

2-Chloro-N-methyl-6-nitrobenzenamine (1.5 g, 8.0 mmol) was dissolved ina mixture of EtOH (15 mL) and H₂O (15 ml). Iron powder (2.2 g, 40 mmol)was added followed by Acetic acid (0.55 mL, 9.6 mmol). The reaction wasmonitored by TLC, after 30 min, the reaction was completed. The reactionmixture was filtered over celite pad and the filtrate was neutralized bysaturated NaHCO₃ (10 mL). The product was extracted by EtOAc (2*10 mL),the organic layer was washed with brine (10 mL), dried over MgSO₄ andconcentrated to dryness to afford 920 mg of6-chloro-N¹-methylbenzene-1,2-diamine (Yield: 73%) as dark brown oil.

Rf (Cyclohexane/EtOAc:70/30)=0.51

LCMS (RT): 2.18 min

191(C) 7-Chloro-2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole

6-Chloro-N¹-methylbenzene-1,2-diamine (800 mg, 5 mmol) and2-chloroacetic acid (700 mg, 8 mmol) were dissolved in HCl 2N (5.7 mL).The resulting solution was heated at 90° C. for 18 h. The aqueous layerwas neutralized by 3N NaOH. After extraction with EtOAc (3*10 mL), theorganic layer was washed with water (10 mL), brine (10 mL) and driedover Na₂SO₄. The solvent was removed under reduced pressure and theresulting crude product was purified over silicagel chromatography(prepacked 25 g silicagel column, Cyclohexane/AcOEt:70/30 as eluent) toafford 478 mg of 7-chloro-2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole(Yield: 40%) as a pink solid

Rf (DCM/MeOH:95/5)=0.35

LCMS (RT): 3.70 min; MS (ES+) gave m/z: 217

191(D)7-Chloro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole

To a solution of the trimethyl(prop-1-ynyl)silane (0.21 mL, 1.4 mmol) inTHF (4 mL), was added at −78° C. nBuLi 2.5M in hexane (0.56 mL, 1.3mmol). After 90 min at −78° C., a solution of7-chloro-2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole (250 mg, 1.2mmol) in THF (2 mL) was added. Mixture went from purple to orange andthen dark brown. The reaction was quenched after 1 h at −78° C. withwater and the solvent was evaporated to dryness to afford 338 mg of7-chloro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole(Yield: 100%) as a brown oily solid. It was carried through to the nextstep without purification.

LCMS (RT): 4.43 min; MS (ES+) gave m/z: 291

191(E) 2-(But-3-ynyl)-7-chloro-1-methyl-1H-benzo[d]imidazole

According to the protocol described in Example 38(D), the conversion of7-chloro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole(338 mg, 1.16 mmol) afforded 116 mg of2-(but-3-ynyl)-7-chloro-1-methyl-1H-benzo[d]imidazole (Yield: 45%) asorange-brown oily solid.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn,

Cyclohexane/AcOEt: from 80/20 to 70/30 as eluent).

LCMS (RT): 2.68 min; MS (ES+) gave m/z: 219

Rf (Cyclohexane/AcOEt:70/30)=0.17

191(F)7-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 190(F), from 2-bromo-6-(fluoromethyl)pyridine (30 mg, 0.16 mmol)and 2-(but-3-ynyl)-7-chloro-1-methyl-1H-benzo[d]imidazole (35 mg, 0.16mmol). The crude residue was purified over silicagel chromatography(prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 99/1 aseluent) to afford 43 mg of a light brown solid. The resulting solid wastriturated into isopropyl ether to give 6 mg of7-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole(Yield: 10%) as white solid.

LCMS (RT): 3.25 min; MS (ES+) gave m/z: 328

Rf (DCM/MeOH:95/5)=0.30

Example 1927-Chloro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole

In a dry reaction tube containing copper iodide (1 mg, 0.0055 mmol) andtriethylamine (0.50 mL, 0.1 mmol), were added 2-iodopyridine (22 mg,0.11 mmol) and Pd(PPh₃)₂Cl₂ (2.4 mg, 0.0055 mmol). A yellow suspensionwas obtained and after a few minutes of stirring at room temperature,2-(but-3-ynyl)-7-chloro-1-methyl-1H-benzo[d]imidazole (compound 191(E),24 mg, 0.11 mmol) in triethylamine (0.2 mL) was added. Immediately thecolor of the reaction turns to black. The mixture was stirred at roomtemperature for 30 min and then at 50° C. for 3 h. Triethylamine wasconcentrated under reduce pressure and the residue was dissolved in DCM.The organic layer was washed with saturated NH₄Cl, water and brine. Thesolvent was removed under reduced pressure and the crude product waspurified by flash chromatography system (prepacked silicagel column 2 g,DCM/MeOH:98/2 as eluent) to afford 2 mg g of7-chloro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole(Yield: 6%) as brown solid.

LCMS (RT): 2.84 min; MS (ES+) gave m/z: 296

Rf (DCM/MeOH:95/5)=0.30

Example 1934,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole193(A) 3,5-Difluoro-N-methyl-2-nitrobenzenamine

1,3,5-Trifluoro-2-nitrobenzene (3.0 g, 16.90 mmol) was dissolved in EtOH(29.7 mL) and Methylamine 40% in Water (1.44 mL, 17.80 mmol) was addeddropwise at 0° C. The color went from bright yellow to an orangeprecipitate within 20 min. After 4 h at RT. 0.66 mL of Methylamine wasadded (9 mmol). To complete the reaction, an additional 0.26 ml (3.6mmol) of Methylamine was added after 2 h at RT. The completion wasachieved within 20 min. Water (75 mL) was added to the reaction mixtureand the solid was isolated by filtration, washed with water (2*10 mL)and dried over high vacuum to afford 2.64 g of3,5-difluoro-N-methyl-2-nitrobenzenamine (Yield: 83%) as an orangesolid.

Rf (Cyclohexane/EtOAc:70/30)=0.57

LCMS (RT): 4.13 min

193(B) 3,5-Difluoro-N¹-methylbenzene-1,2-diamine

The title compound was prepared in accordance with the general method ofExample 191(B), from 3,5-difluoro-N-methyl-2-nitrobenzenamine (1.5 g, 8mmol) to afford 933 mg of 3,5-difluoro-N¹-methylbenzene-1,2-diamine(Yield: 74%) as a deep purple oily liquid.

Rf (DCM/MeOH: 95/5)=0.66

193(C) 2-(Chloromethyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 191(C), from 3,5-difluoro-N¹-methylbenzene-1,2-diamine (1.50 g,9.50 mmol) and 2-chloroacetic acid (1.3 g, 14 mmol). The crude residuewas purified over silicagel chromatography (prepacked 25 g silicagelcolumn, Cyclohexane/AcOEt:70/30 as eluent) to afford 443 mg of2-(chloromethyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (Yield: 22%)as a purple solid.

LCMS (RT): 3.46 min; MS (ES+) gave m/z: 217

Rf (DCM/MeOH:95/5)=0.43

193(D)4,6-Difluoro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 191(D), from2-(chloromethyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (440 mg,2.03 mmol) and trimethyl(prop-1-ynyl)silane (274 mg, 2.44 mmol).4,6-difluoro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole(539 mg, Yield: 91%) was obtained as a brown oil which can be used inthe next step without any purification.

LCMS (RT): 4.67 min; MS (ES+) gave m/z: 293

193(E) 2-(But-3-ynyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole

According to the protocol described in Example 38(D), the conversion of4,6-difluoro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole(539 mg, 1.84 mmol) afforded 126 mg of2-(but-3-ynyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (Yield: 31%)as an orange solid.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn,

Cyclohexane/AcOEt: from 80/20 to 70/30).

LCMS (RT): 3.22 min; MS (ES+) gave m/z: 221

193(F)4,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 190(F), from 2-bromo-6-(fluoromethyl)pyridine (109 mg, 0.57 mol)and 2-(but-3-ynyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (126 mg,0.57 mmol). The crude residue was purified over silicagel chromatography(prepacked 25 g silicagel column, DCM/MeOH: from 100/0 to 99/1 aseluent) to afford 43 mg of a light brown solid. The resulting solid wasdissolved in Dioxane and 0.5N HCl in dioxan was added (0.14 mL, 0.07mmol). A green solid was formed and it was collected by filtration andwashed with AcOEt. The chlorhydrate salt was dissolved in MeOH,neutralized by saturated NaHCO₃. The aqueous layer was extracted twicewith AcOEt. The organic layer was dried over MgSO₄ and the solventremoved under reduced pressure to afford 9 mg of4,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole(Yield: 5%) as purple oily solid (Mp=103° C.-104° C.).

LCMS (RT): 3.68 min; MS (ES+) gave m/z: 330

Rf (DCM/MeOH: 95/5)=0.36

¹H-NMR (CDCl₃), δ (ppm): 7.70-7.60 (t, 1H), 7.40-7.30 (d, 1H), 7.30-7.20(d, 1H), 6.80-6.60 (m, 2H), 5.46-5.31 (d, 2H), 3.68 (s, 3H), 3.18-3.12(m, 2H), 3.02-2.95 (m, 2H)

Example 1941-Isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole 194(A)N-Isopropyl-2-nitrobenzenamine

To a solution of 1-fluoro-2-nitrobenzene (4.406 g, 31.22 mmol) in EtOH(32 mL) was added at 0° C. isopropyl amine (2.97 mL, 32.80 mmol). Themixture turned from light yellow to bright orange instantly. It wasstirred overnight at RT. Another 1 eq of isopropyl amine (2.97 mL, 32.80mmol) was added and after 3 h of stiffing 2 eq of isopropyl amine wereadded (6 mL, 64 mmol) and the resulting solution was kept at roomtemperature overnight. The reaction mixture was concentrated and anotherequivalent of isopropyl amine was added (2.97 mL) following by EtOH (2mL). For completion, the reaction was heated at 50° C. for 2 h. Mixturewas evaporated to dryness and dissolved in EtOAc (25 mL) and theoraganic phase was washed with water (3*10 mL). Aqueous phase wasre-extracted with EtOAc (10 mL) and the combined organics were washedwith brine and dried over Na₂SO₄. The solvent was evaporated underreduced pressure to afford 5.24 g of N-isopropyl-2-nitrobenzenamine(Yield: 93%) as an orange liquid

Rf (Cyclohexane/AcOEt:70/30)=0.67

LCMS (RT): 4.58 min

194(B) N¹-Isopropylbenzene-1,2-diamine

The title compound was prepared in accordance with the general method ofExample 191(B), from N-isopropyl-2-nitrobenzenamine (5.24 g, 29.1 mmol)to afford 3.88 g of N¹-isopropylbenzene-1,2-diamine (Yield: 89%) as adark brown liquid.

Rf (Cyclohexane/AcOEt:70/30)=0.36

LCMS (RT): 1.68 min; MS (ES+) gave m/z: 151

194(C) 2-(Chloromethyl)-1-isopropyl-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 191(C), from N¹-isopropylbenzene-1,2-diamine (3.88 g, 25.82mmol) and 2-chloroacetic acid (3.70 g, 39 mmol). The crude residue waspurified over silicagel chromatography (prepacked 85 g silicagel column,Cyclohexane/AcOEt:70/30 as eluent) to afford 2.05 g of2-(chloromethyl)-1-isopropyl-1H-benzo[d]imidazole (Yield: 38%) as alight brown oil.

LCMS (RT): 2.88 min; MS (ES+) gave m/z: 209

Rf (Cyclohexane/AcOEt:70/30)=0.27

¹H-NMR (CDCl₃), δ (ppm): 7.74-7.64 (m, 1H), 7.55-7.45 (m, 1H), 7.25-7.16(m, 2H), 4.80-4.70 (m, 3H), 1.64-1.55 (d, 6H).

194(D) 1-Isopropyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 191(D), from of2-(chloromethyl)-1-isopropyl-1H-benzo[d]imidazole (500 mg, 2.4 mmol) andtrimethyl(prop-1-ynyl)silane (323 mg, 2.88 mmol).1-isopropyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (680mg, Yield: 100%) was obtained as a brown oil which was used in the nextstep without any purification.

LCMS (RT): 3.27 min; MS (ES+) gave m/z: 285

194(E) 2-(But-3-ynyl)-1-isopropyl-1H-benzo[d]imidazole

According to the protocol described in Example 38(D), the conversion of1-isopropyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (680mg, 2.39 mmol) afforded 84 mg of2-(but-3-ynyl)-1-isopropyl-1H-benzo[d]imidazole (Yield: 17%) as anorange solid. Purification over silicagel chromatography (prepacked 25 gsilicagel column, Cyclohexane/AcOEt: from 80/20 to 70/30).

LCMS (RT): 2.32 min; MS (ES+) gave m/z: 213

¹H-NMR (CDCl₃), δ (ppm): 7.75-7.63 (m, 1H), 7.54-7.43 (m, 1H), 7.27-7.15(m, 2H), 4.70-4.63 (m, 1H), 3.14-3.00 (m, 2H), 2.81-2.74 (m, 2H), 1.92(s, 1H), 1.66-1.55 (d, 6H).

194(F) 1-Isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 192(A), from 2-iodopyridine (81 mg, 0.39 mmol) and2-(but-3-ynyl)-1-isopropyl-1H-benzo[d]imidazole (84 mg, 0.39 mmol). Thecrude residue was purified over silicagel chromatography (prepacked 5 gsilicagel column, DCM/MeOH: from 100/0 to 96/4 as eluent) to afford 47mg of 1-isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole asa light brown oil (Yield: 41%).

LCMS (RT): 2.42 min; MS (ES+) gave m/z: 290

¹H-NMR (CDCl₃), δ (ppm): 8.55-8.45 (d, 1H), 7.80-7.05 (m, 7H),4.80-4.57-(m, 1H), 3.30-2.92 (m, 4H), 1.69-1.50 (d, 6H).

Example 1951-Phenethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole 195(A)2-Nitro-N-phenethylbenzenamine

To a solution of 1-fluoro-2-nitrobenzene (4.4 g, 31.2 mmol) in EtOH (32mL) was added at 0° C., 2-phenylethanamine (4.11 mL, 32.8 mmol). Mixturewent from light yellow to bright orange instantly and it was stirringovernight at RT. Another equivalent of 2-phenylethanamine was added(4.11 mL, 32.8 mmol) and the mixture was heated to 50° C. overnight.Water was added (20 ml) and the resulting orange solid was isolated byfiltration to afford 6.99 g of 2-nitro-N-phenethylbenzenamine (Yield:92%) as an orange crystalline solid.

LCMS (RT): 4.95 min; MS (ES+) gave m/z: 243

195(B) N¹-Phenethylbenzene-1,2-diamine

The title compound was prepared in accordance with the general method ofExample 191(B), from 2-nitro-N-phenethylbenzenamine (6.99 g, 28.9 mmol)to afford 5.66 g of N¹-phenethylbenzene-1,2-diamine (Yield: 92%) as abrown oily solid.

Rf (Cyclohexane/AcOEt:70/30)=0.41

LCMS (RT): 3.03 min; MS (ES+) gave m/z: 213

195(C) 2-(Chloromethyl)-1-phenethyl-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 191(C), from N¹-phenethylbenzene-1,2-diamine (2.57 g, 12.11mmol) and 2-chloroacetic acid (1.70 g, 18 mmol). The crude residue waspurified over silicagel chromatography (prepacked 70 g silicagel column,Cyclohexane/AcOEt: from 80/20 to 70/30 as eluent) to afford 2.02 g of2-(chloromethyl)-1-phenethyl-1H-benzo[d]imidazole (Yield: 61%) as awhite crystalline solid.

LCMS (RT): 3.88 min; MS (ES+) gave m/z: 271

Rf (Cyclohexane/AcOEt:70/30)=0.18

195(D) 1-Phenethyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 191(D), from of2-(chloromethyl)-1-phenethyl-1H-benzo[d]imidazole (500 mg, 1.8 mmol) andtrimethyl(prop-1-ynyl)silane (249 mg, 2.22 mmol).1-phenethyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (639mg, Yield: 100%) was obtained as a brown oil which was used in the nextstep without purification.

LCMS (RT): 3.90 min; MS (ES+) gave m/z: 347

195(E) 2-(But-3-ynyl)-1-phenethyl-1H-benzo[d]imidazole

According to the protocol described in Example 38(D), the conversion of1-phenethyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (639mg, 1.84 mmol) afforded 62 mg of2-(but-3-ynyl)-1-phenethyl-1H-benzo[d]imidazole (Yield: 12%) as anorange oily solid. Purification over silicagel chromatography (prepacked25 g silicagel column, Cyclohexane/AcOEt:70/30).

LCMS (RT): 3.07 min; MS (ES+) gave m/z: 275

¹H-NMR (CDCl₃), δ (ppm): 7.70-7.63 (m, 1H), 7.28.7.12 (m, 6H), 7.27-7.15(m, 2H), 4.35-4.25 (t, 2H), 3.08-2.95 (t, 2H), 2.65-2.55 (m, 4H), 1.90(s, 1H).

195(F) 1-Phenethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 192(A), from 2-iodopyridine (46 mg, 0.22 mmol) and2-(but-3-ynyl)-1-phenethyl-1H-benzo[d]imidazole (62 mg, 0.22 mmol). Thecrude residue was purified over silicagel chromatography (prepacked 5 gsilicagel column, DCM/MeOH: from 100/0 to 96/4 as eluent) to afford 20mg of 1-phenethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole asa light brown oil (Yield: 25%).

LCMS (RT): 3.00 min; MS (ES+) gave m/z: 352

¹H-NMR (CDCl₃), δ (ppm): 8.50-8.45 (d, 1H), 7.72-7.65 (m, 1H), 7.58-7.48(t, 1H), 7.31-7.10 (m, 8H), 6.93-6.86 (m, 2H), 4.37-4.25 (t, 2H),3.08-2.95 (t, 2H), 2.86-2.68 (m, 4H).

Example 196 1-Benzyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole196(A) N-Benzyl-2-nitrobenzenamine

The title compound was prepared in accordance with the general method ofExample 195(A), from phenylmethanamine (3.51 g, 32.78 mmol) and1-fluoro-2-nitrobenzene (4.40 g, 31.22 mmol). 6.65 g ofN-benzyl-2-nitrobenzenamine (Yield: 93%) was obtained as an orangecrystalline solid which was used without further purification.

LCMS (RT): 3.70 min; MS (ES+) gave m/z: 229

196(B) N¹-Benzylbenzene-1,2-diamine

The title compound was prepared in accordance with the general method ofExample 191(B), from N-benzyl-2-nitrobenzenamine (6.65 g, 29.1 mol) toafford 4.66 g of M-benzylbenzene-1,2-diamine (Yield: 80%) as a brown oilwhich was used in the next step without further purification.

Rf (Cyclohexane/AcOEt:70/30)=0.45

LCMS (RT): 2.83 min; MS (ES+) gave m/z: 199

196(C) 1-Benzyl-2-(chloromethyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 191(C), from M-benzylbenzene-1,2-diamine (2.93 g, 14.78 mmol)and 2-chloroacetic acid (2.10 g, 22 mmol). The crude residue waspurified over silicagel chromatography (prepacked 70 g silicagel column,Cyclohexane/AcOEt: from 80/20 to 70/30 as eluent) to afford 2.34 g of1-benzyl-2-(chloromethyl)-1H-benzo[d]imidazole (Yield: 61%) as a yellowoil.

LCMS (RT): 3.87 min; MS (ES+) gave m/z: 257

Rf (Cyclohexane/AcOEt:70/30)=0.28

196(D) 1-Benzyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 191(D), from of 1-benzyl-2-(chloromethyl)-1H-benzo[d]imidazole(500 mg, 1.9 mmol) and trimethyl(prop-1-ynyl)silane (262 mg, 2.34 mmol).1-benzyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (647 mg,Yield: 100%) was obtained as a brown oil which was used in the next stepwithout purification.

LCMS (RT): 3.83 min; MS (ES+) gave m/z: 333

196(E) 1-Benzyl-2-(but-3-ynyl)-1H-benzo[d]imidazole

According to the protocol described in Example 38(D), the conversion of1-benzyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (647 mg,1.94 mmol) afforded 41 mg of1-benzyl-2-(but-3-ynyl)-1H-benzo[d]imidazole (Yield: 8%) as orange oilysolid. Purification over silicagel chromatography (prepacked 25 gsilicagel column, Cyclohexane/AcOEt: from 80/20 to 70/30).

LCMS (RT): 2.80 min; MS (ES+) gave m/z: 261

¹H-NMR (CDCl₃), δ (ppm): 7.75-7.63 (m, 1H), 7.30.7.10 (m, 7H), 7.00-6.95(m, 1H), 5.30 (s, 2H), 3.05-2.95 (t, 2H), 2.70-2.80 (t, 2H), 1.92 (s,1H)

196(F) 1-Benzyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 192(A), from 2-iodopyridine (38 mg, 0.18 mmol) and1-benzyl-2-(but-3-ynyl)-1H-benzo[d]imidazole (49 mg, 0.18 mmol). Thecrude residue was purified over silicagel chromatography (prepacked 2 gsilicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 15mg of 1-benzyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as ayellow oily solid (Yield: 23%).

LCMS (RT): 2.90 min; MS (ES+) gave m/z: 338

¹H-NMR (CDCl₃), δ (ppm): 8.50 (d, 1H), 7.70-7.65 (d, 1H), 7.55-7.44 (t,1H), 7.25-7.05 (m, 8H), 7.00-6.88 (m, 2H), 5.30 (s, 2H), 3.14-3.07 (m,2H), 3.05-2.92 (m, 2H)

Example 1975-Fluoro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole197(A) 4-Fluoro-N-methyl-2-nitrobenzenamine

1,4-Difluoro-2-nitrobenzene (2.63 g, 16.53 mmol) was dissolved in EtOH(9 mL) and Methylamine 40% in Water (9 mL) was added dropwise at 0° C.and the mixture was warming up to RT overnight. 75 mL of water was addedto the reaction mixture and the orange solid was filtered and washedwith water (2*10 ml) to afford 2.78 g of4-fluoro-N-methyl-2-nitrobenzenamine (Yield: 99%) as an orangecrystalline solid.

Rf (Cyclohexane/AcOEt:80/20)=0.34

LCMS (RT): 4.03 min; MS (ES+) gave m/z: 171

197(B) 4-Fluoro-N¹-methylbenzene-1,2-diamine

The title compound was prepared in accordance with the general method ofExample 191(B), from 4-fluoro-N-methyl-2-nitrobenzenamine (1.5 g, 8.8mmol) to afford 1.08 g of 4-fluoro-N¹-methylbenzene-1,2-diamine (Yield:88%) as a brown oil which was used in the next step withoutpurification.

Rf (DCM/MeOH: 95/5)=0.61

LCMS (RT): 0.84 min; MS (ES+) gave m/z: 141

197(C) 2-(Chloromethyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 191(C), from 4-fluoro-N¹-methylbenzene-1,2-diamine (2.5 g, 17.84mmol) and 2-chloroacetic acid (2.50 g, 27 mmol). The crude residue waspurified over silicagel chromatography (prepacked 70 g silicagel column,Cyclohexane/AcOEt:60/40 as eluent) to afford 277 mg of2-(chloromethyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole (Yield: 8%) as asemi-solid.

LCMS (RT): 2.88 min; MS (ES+) gave m/z: 199

Rf (DCM/MeOH: 95/5)=0.29

197(D)5-Fluoro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 191(D), from of2-(chloromethyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole (270 mg, 1.36mmol) and trimethyl(prop-1-ynyl)silane (183 mg, 1.63 mmol). The cruderesidue was used in the next step without any purification.5-fluoro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole(373 mg, Yield: 100%) as a brown oil.

LCMS (RT): 3.37 min; MS (ES+) gave m/z: 275

Rf (DCM/MeOH:95/5)=0.36

197(E) 2-(But-3-ynyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole

According to the protocol described in Example 38(D), the conversion of5-fluoro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole(373 mg, 1.35 mmol) afforded 73 mg of2-(but-3-ynyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole (Yield: 26%) as anorange solid. Purification over silicagel chromatography (prepacked 25 gsilicagel column, Cyclohexane/AcOEt: from 80/20 to 70/30).

LCMS (RT): 1.85 min; MS (ES+) gave m/z: 203

¹H-NMR (CDCl₃), δ (ppm): 7.40-6.95 (m, 3H), 3.70 (s, 3H), 3.10-3.00 (m,2H), 2.80-2.70 (m, 2H), 1.95 (m, 1H)

197 (F)5-Fluoro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole

The title compound was prepared in accordance with the general method ofExample 192(A), from 2-iodopyridine (74 mg, 0.36 mmol) and2-(but-3-ynyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole (73 mg, 0.36mmol). The crude residue was purified over silicagel chromatography(prepacked 2 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent)to afford 28 mg of5-fluoro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole asa orange oily solid (Yield: 27%).

LCMS (RT): 2.35 min; MS (ES+) gave m/z: 280

Rf (DCM/MeOH:95/5)=0.37

¹H-NMR (CDCl₃), δ (ppm): 8.50 (d, 1H), 7.62-7.50 (t, 1H), 7.33-7.25 (m,2H), 7.18-7.05 (m, 2H), 7.00-6.90 (t, 1H), 3.70 (s, 3H), 3.22-3.11 (m,2H), 3.02-2.95 (m, 2H)

Example 198 1-(4-(Pyridin-2-yl)but-3-ynyl)pyridin-2(1H)-one 198(A)4-Bromobut-1-ynyl)trimethylsilane

To a solution of 3-butyn-1-ol (4 g, 57 mmol) in THF (0.7M, 80 mL)) at−78° C. was added 2.1N n-BuLi in hexane (52 mL, 110 mmol). After 1 h at−78° C., the reaction mixture was treated with chlorotrimethylsilane (13g, 120 mmol) and the resulting mixture was warmed to room temperatureover 2 h. The reaction mixture was quenched with water, extracted withEt₂O, and concentrated. The concentrate was treated with HCl 3N,extracted with Et₂O (3×), washed with saturated aqueous NaHCO₃ (3×) andNaCl (1×), dried (MgSO₄), and concentrated. The crude product wasdiluted in THF (50 mL), the solution was cooled to −78° C. before theaddition of 26 mL of n-BuLi 2.1N in hexane (52 mmol.). After 1 h at −78°C. p-toluenesulfonyl chloride (12 g, 63 mmol.) in THF solution (35 mL)was added. The reaction mixture was stirred over night at roomtemperature. The reaction mixture was treated with water, followed byextraction with ether, washing with saturated aqueous NaHCO₃, with NaCl,dried (MgSO₄) and concentrated The crude product was dissolved inacetone (100 mL) containing LiBr (5 g, 57 mmol.) and the reactionmixture was stirred at room temperature for 5 h. The reaction mixturewas poured into water. Extraction with pentane (4×), washing withsaturated aqueous NaHCO₃ and NaCl, drying (MgSO₄), concentration to give7.50 g of 4-bromobut-1-ynyl)trimethylsilane (Yield: 64%) as a brown oilwhich was used in the next step without further purification.

198(B) 1-(But-3-ynyl)pyridin-2(1H)-one

4-bromobut-1-ynyl)trimethylsilane (700 mg, 3 mmol), pyridin-2-ol (300mg, 3 mmol) and K₂CO₃ (900 mg, 6 mmol) were poured into acetone (4.2 ml)and the resulting mixture was heated in the microwave at 150° C. for 7min. The solvent was evaporated and the crude product was dissolved DCMand the organic layer was washed with water. The crude residue waspurified over silicagel chromatography (prepacked 5 g silicagel column,DCM/MeOH: 99/1 as eluent) to afford 33 mg of1-(but-3-ynyl)pyridin-2(1H)-one as a brown oil (Yield: 5%).

LCMS (RT): 2.20 min; MS (ES+) gave m/z: 148

Rf (DCM/MeOH: 95/5)=0.19

¹H-NMR (CDCl₃), δ (ppm): 7.35-7.25 (m, 2H), 6.55-6.45 (d, 1H), 6.15-6.05(t, 1H), 4.00-3.93 (t, 2H), 2.58-2.64 (m, 2H), 1.95-1.90 (t, 1H)

198(C) 1-(4-(Pyridin-2-yl)but-3-ynyl)pyridin-2(1H)-one

The title compound was prepared in accordance with the general method ofExample 192(A), from 2-iodopyridine (50 mg, 0.2 mmol) and1-(but-3-ynyl)pyridin-2(1H)-one (33 mg, 0.2 mmol). The crude residue waspurified over silicagel chromatography (prepacked 10 g silicagel column,DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 10 mg of1-(4-(pyridin-2-yl)but-3-ynyl)pyridin-2(1H)-one as a yellow oil (Yield:20%).

LCMS (RT): 2.22 min; MS (ES+) gave m/z: 225

¹H-NMR (CDCl₃), δ (ppm): 8.55-8.45 (m, 1H), 7.62-7.50 (t, 1H), 7.41-7.12(m, 4H), 6.55-6.45 (m, 1H), 6.10-6.05 (t, 1H), 4.10-4.05 (t, 2H),2.90-2.80 (t, 2H)

Example 199 3-Methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide199(A) 4-(Pyridin-2-yl)but-3-yn-1-ol

To a suspension of CuI (301 mg, 1.58 mmol) in TEA (40 mL) were added2-bromopyridine (5 g, 31.6 mmol), followed by Pd₂Cl₂(PPh₃)₂ (1.11 g,1.58 mmol) to give a yellow orange suspension. After cooling down to 0°C. under N₂, 3-butyn-1-ol (2.28 g, 31.6 mmol) was added. The resultingreaction mixture turned black and it was stirred overnight at 70° C. Thereaction mixture was quenched at 0° C. with water, TEA was removed underlow pressure, and the organic layer was extracted 3× using DCM, washedwith Ammonia, water, brine, dried over MgSO₄, filtered and concentrated.The crude residue was purified over silicagel chromatography (prepacked250 g silicagel column, DCM/MeOH: from 99/1 to 95/5 as eluent) to afford3.60 g of 4-(pyridin-2-yl)but-3-yn-1-ol as a brown oil (Yield: 77%).

LCMS (RT): 1.58 min; MS (ES+) gave m/z: 148

Rf (DCM/MeOH: 95/5)=0.23

199(B) 4-(Pyridin-2-yl)but-3-ynyl methanesulfonate

To a stirred solution of 4-(pyridin-2-yl)but-3-yn-1-ol (3.60 g, 24 mmol)in dry methylene chloride (30 mL) was added triethylamine (4.40 mL, 32mmol). The mixture was cooled at 4° C. and methanesulfonyl chloride(2.50 mL, 32 mmol) was added and the reaction was stirred at roomtemperature overnight. The reaction mixture was then poured overice/water (100 mL) and stirred for 5 min. To this mixture was addedsaturated aqueous sodium bicarbonate solution (50 mL) chilled to 4° C.,and the mixture was stirred for 30 min, then extracted with DCM. Thecombined organic fractions were dried over MgSO₄, filtered andconcentrated under pressure to afford 4.60 g of4-(pyridin-2-yl)but-3-ynyl methanesulfonate (Yield: 83%) as a brown oilwhich can be used in the next step without further purification.

LCMS (RT): 2.43 min; MS (ES+) gave m/z: 226

Rf (DCM/MeOH:95/5)=0.6

199(C)N-Methyl-4-(pyridin-2-yl)but-3-yn-1-amine

4-(Pyridin-2-yl)but-3-ynyl methanesulfonate (2.90 g, 12.87 mmol) wasdissolved in methylamine 40% in aqueous solution (20 mL) and stirred for3 hoursunder nitrogen at 45° C. The reaction mixture was cooled withice, quenched with water and extracted with DCM. The organic phases werewashed with brine, dried over MgSO₄ and concentrated. The crude residuewas purified over silicagel chromatography (prepacked 70 g silicagelcolumn, DCM/MeOH: from 90/10 to 90/10 with 1% of TEA as eluent) toafford 817 mg N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (Yield: 39%) asa brown oil

LCMS (RT): 0.65 min; MS (ES+) gave m/z: 161

¹H-NMR (CDCl₃), δ (ppm): 8.55-8.52 (m, 1H), 7.58-7.68 (t, 1H), 7.43-7.38(d, 1H), 7.23-7.18 (d, 1H), 2.90-2.82 (t, 2H), 2.70-2.63 (t, 2H), 2.48(s 3H)

199(D) 3-Methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

N-Methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) wasdissolved in DCM (2 mL) and DIEA (67 μl, 0.41 mmol) was added at roomtemperature. The resulting mixture was cooled to 0° C. before theaddition of 3-methoxybenzoyl chloride (69 mg, 0.41 mmol). After stirringovernight at room temperature, the mixture was quenched with water andextracted with DCM. DCM fractions were washed with water (10 mL), NaHCO₃sat (2*10 mL), water (10 mL), brine (10 mL). The solvent was removed andthe crude residue was purified over silicagel chromatography (prepacked10 g silicagel column, DCM/MeOH: from 100/0 to 95/5 as eluent) to afford58 mg of 3-methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide(Yield: 63%) as a brown oil.

LCMS (RT): 3.17 min; MS (ES+) gave m/z: 295

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=57/43 ratio: 8.56-8.44 (m, 1H),7.64-7.52 (m, 2H), 7.36-7.08 (m, 2H), 6.96-6.80 (m, 3H), 3.80-3.65 (s,3H and m, 2H, conformer A), 3.75-3.40 (t, 2H, conformers B), 3.10-2.98(2s, 3H, conformer A and B), 2.85-2.70 (t, 2H, conformer A), 2.65-2.50(t, 2H, conformer B)

Example 200 3-Fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 3-fluorobenzoyl chloride (64 mg, 0.41 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 34mg of 3-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as abrown oil (Yield: 39%).

LCMS (RT): 3.21 min; MS (ES+) gave m/z: 283

Rf (DCM/MeOH:95/5)=0.22

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=60/40 ratio: 8.55-8.45 (d, 1H),7.62-7.50 (t, 1H), 7.35-7.22 (m, 2H), 7.18-6.95 (m, 4H), 3.78-3.63 (s,2H, conformer A), 3.60-3.50 (s, 2H, conformer B), 3.10-2.95 (2s, 3Hconformers A+B), 2.85-2.70 (s, 2H, conformer A), 2.68-2.50 (s, 2H,conformer B)

Example 201 N-Methyl-2-phenyl-N-(4-(pyridin-2-yl)but-3-ynyl)acetamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 2-phenylacetyl chloride (60 mg, 0.41 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 64mg of N-methyl-2-phenyl-N-(4-(pyridin-2-yl)but-3-ynyl)acetamide as abrown oil (Yield: 74%).

LCMS (RT): 3.15 min; MS (ES+) gave m/z: 279

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=63/37 ratio: 8.55-8.45 (m, 1H),7.62-7.52 (t, 1H), 7.38-7.12 (m, 7H), 3.80 (s, 2H, conformer B), 3.70(s, 2H, conformer A), 3.65-3.55 (m, 2H), 3.10 (s, 3H, conformer A), 2.95(s, 3H, conformer B), 2.70 (t, 2H, conformer A), −2.53 (t, 2H, conformerB)

Example 202N-Methyl-N-(4-(pyridin-2-yl)but-3-ynyl)-2-(trifluoromethyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 2-(trifluoromethyl)benzoyl chloride (80 mg, 0.41 mmol).The crude residue was purified over silicagel chromatography (prepacked10 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford63 mg ofN-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)-2-(trifluoromethyl)benzamide asa brown oil (Yield: 61%).

LCMS (RT): 3.57 min; MS (ES+) gave m/z: 333

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=65/35 ratio: 8.55-8.45 (d, 1H),7.65-7.10 (m, 7H), 3.90-3.60 (m, 2H, conformer A), 3.45-3.20 (m, 2H,conformer B), 3.10 (s, 3H, conformer B), 2.85 (s, 3H, conformer A),2.80-2.70 (m, 2H, conformer A), 2.60-2.50 (m, 2H, confomer B).

Example 203 4-Fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg,0.62 mmol) and 4-fluorobenzoyl chloride (99 mg, 0.62 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH:98/2 as eluent) to afford 103 mg of4-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil(Yield: 58%).

LCMS (RT): 3.03 min; MS (ES+) gave m/z: 283

Rf (DCM/MeOH:95/5)=0.41

¹H-NMR (CDCl₃), δ (ppm): 8.55-8.45 (m, 1H), 7.65-7.58 (m, 1H), 7.48-7.32(m, 3H), 7.23-7.18 (m, 1H), 7.10-7.02 (m, 2H), 3.85-3.50 (m, 2H), 3.10(s, 3H), 2.90-2.60 (m, 2H).

Example 204 2-Chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg,0.62 mmol) and 2-chlorobenzoyl chloride (109 mg, 0.62 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: 98/2 as eluent) to afford 118 mg of2-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil(Yield: 63%).

LCMS (RT): 3.20 min; MS (ES+) gave m/z: 299

Rf (DCM/MeOH: 95/5)=0.42

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=59/41 ratio: 8.55-8.45 (m, 1H),7.65-7.58 (t, 1H), 7.43-7.15 (m, 6H), 3.95-3.40 (m, 2H), 3.20 (s, 3H,conformer B), 2.95 (s, 3H, conformer A), 2.90-2.83 (m, 2H, conformer A),2.68-2.60 (m, 2H, conformer B).

Example 205 3-Chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg,0.62 mmol) and 3-chlorobenzoyl chloride (109 mg, 0.62 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: 98/2 as eluent) to afford 112 mg of3-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil(Yield: 60%).

LCMS (RT): 3.35 min; MS (ES+) gave m/z: 299

Rf (DCM/MeOH:95/5)=0.42

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=63/37 ratio: 8.55-8.45 (m, 1H),7.60-7.50 (t, 1H), 7.40-7.10 (m, 6H), 3.90-3.70 (m, 2H, conformer A),3.60-3.50 (m, 2H, conformer B), 3.05 (s, 3H), 2.90-2.80 (m, 2H,conformer A), 2.75-2.60 (m, 2H, conformer B).

Example 2064-Fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg,0.62 mmol) and 4-fluorobenzene-1-sulfonyl chloride (121 mg, 0.62 mmol).The crude residue was purified over silicagel chromatography (prepacked10 g silicagel column, DCM/MeOH:98/2 as eluent) to afford 32 mg of4-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide as ayellow oil (Yield: 16%).

LCMS (RT): 3.70 min; MS (ES+) gave m/z: 319

¹H-NMR (CDCl₃), δ (ppm): 8.55-8.45 (m, 1H), 7.85-7.75 (t, 2H), 7.60-7.50(t, 1H), 7.30 (d, 1H), 7.20-7.00 (m, 3H), 3.30-3.20 (t, 2H), 2.80 (s,3H), 2.70-2.60 (m, 2H).

Example 2072-Chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 2-chlorobenzene-1-sulfonyl chloride (79 mg, 0.37 mmol).The crude residue was purified over silicagel chromatography (prepacked10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford37 mg of2-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide as abrown oil (Yield: 35%).

Rf (DCM/MeOH: 95/5)=0.51

LCMS (RT): 3.78 min; MS (ES+) gave m/z: 335

¹H-NMR (CDCl₃), δ (ppm): 8.55-8.45 (m, 1H), 8.15-8.05 (d, 1H), 7.68-7.60(t, 1H), 7.55-7.35 (m, 4H), 7.23-7.15 (m, 1H), 3.60-3.50 (t, 2H), 3.00(s, 3H), 2.80-2.70 (t, 2H).

Example 2082-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide208(A) 4-(6-(Fluoromethyl)pyridin-2-yl)but-3-yn-1-ol

The title compound was prepared in accordance with the general method ofExample 199(A), from 2-bromo-6-(fluoromethyl)pyridine (compound 190(E),3.50 g, 18 mmol) and 3-butyn-1-ol (1.3 g, 18 mmol). The crude residuewas purified over silicagel chromatography (prepacked 85 g silicagelcolumn, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 2.60 g of4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-ol as an orange solid (Yield:79%).

Rf (DCM/MeOH: 95/5)=0.31

LCMS (RT): 2.52 min; MS (ES+) gave m/z: 180

208(B) 4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl methanesulfonate

The title compound was prepared in accordance with the general method ofExample 199(B), from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-ol (2.60g, 15 mmol) and methanesulfonyl chloride (1.50 mL, 19 mmol) to afford2.90 g of 4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl methanesulfonate(Yield: 78%) as a pale yellow oil which was used in the next stepwithout further purification.

Rf (DCM/MeOH: 95/5)=0.60

LCMS (RT): 3.28 min; MS (ES+) gave m/z: 258

208C) 4-(6-(Fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine

The title compound was prepared in accordance with the general method ofExample 199(C), from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynylmethanesulfonate (2.90 g, 11 mmol) and N-methylamine 40% in aqueoussolution (20 mL). The crude residue was purified over silicagelchromatography (prepacked 70 g silicagel column, DCM/MeOH: from 90/10 to90/10 with 1% TEA as eluent) to afford 324 mg of4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine as a pale oil(Yield: 15%).

LCMS (RT): 0.65-71.83 min; MS (ES+) gave m/z: 193

208(D)2-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (70 mg, 0.36mmol) and 2-chlorobenzoyl chloride (76 mg, 0.44 mmol). The crude residuewas purified over silicagel chromatography (prepacked 10 g silicagelcolumn, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 37 mg of2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamideas a brown oil (Yield: 31%).

LCMS (RT): 3.82 min; MS (ES+) gave m/z: 331

Rf (DCM/MeOH: 95/5)=0.25

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=61/39 ratio: 7.75-7.65 (t, 1H),7.45-7.23 (m, 6H), 5.60-5.35 (2d, 2H, conformer A+B), 3.95-3.70 (m, 2H,conformer A), 3.50-3.40 (m, 2H, conformer B), 3.20 (s, 3H, conformer B),2.95 (s, 3H, conformer A), 2.90-2.82 (t, 2H, conformer A), 2.70-2.60 (t,2H, conformer B)

Example 2092-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzenesulfonamide

The title compound was prepared in accordance with the general method ofExample 199(D), from4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (70 mg, 0.36mmol) and 2-chlorobenzene-1-sulfonyl chloride (92 mg, 0.44 mmol). Thecrude residue was purified over silicagel chromatography (prepacked 10 gsilicagel column, Cyclohexane/AcOEt:70/30 as eluent) to afford 41 mg of2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzenesulfonamideas a yellow oil (Yield: 31%).

Rf (Cyclohexane/AcOEt:70/30)=0.26

LCMS (RT): 4.30 min; MS (ES+) gave m/z: 367

¹H-NMR (CDCl₃), δ (ppm): 8.10 (d, 1H), 7.75-7.65 (t, 1H), 7.52-7.30 (m,5H), 5.53-5.38 (d, 2H), 3.60-3.50 (t, 2H), 3.00 (s, 3H), 2.80-2.70 (t,2H)

Example 2102,6-Dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (180 mg, 0.93mmol) and 2,6-dichlorobenzoyl chloride (255 mg, 1.22 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 18.5mg of2,6-dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamideas a yellow oil (Yield: 5%).

Rf (Cyclohexane/AcOEt:70/30)=0.26

LCMS (RT): 3.93 and 4.04 min; MS (ES+) gave m/z: 365

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=90/10 ratio: 7.75-7.65 (t, 1H),7.48-7.20 (m, 5H), 5.60-5.35 (2d, 2H, comformers A+B), 3.80-3.70 (t, 2H,comformer A), 3.50-3.40 (t, 2H, conformer B), 3.22 (s, 3H, conformer B),2.98 (s, 3H, conformer A), 2.95-2.85 (t, 2H, conformer A), 2.75-2.65 (t,2H, conformer B)

Example 211 N-Methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and benzoyl chloride (53 mg, 0.37 mmol). The crude residuewas purified over silicagel chromatography (prepacked 10 g silicagelcolumn, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 30 mg ofN-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamideas a brown oil (Yield:36%).

Rf (DCM/MeOH: 95/5)=0.31

LCMS (RT): 2.92 min; MS (ES+) gave m/z: 265

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=59/41 ratio: 8.55-8.45 (m, 1H),7.60-7.50 (t, 1H), 7.40-7.10 (m, 7H), 3.80-3.60 (m, 2H, conformer A),3.55-3.40 (m, 2H, conformer B), 3.15-3.10 (2s, 3H), 2.85-2.70 (m, 2H,conformer A), 2.65-2.50 (m, 2, conformer B).

Example 212

N,2-Dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 2-methylbenzoyl chloride (58 mg, 0.37 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 32.5mg of N,2-dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brownoil (Yield: 37%).

LCMS (RT): 3.15 min; MS (ES+) gave m/z: 279

Rf (DCM/MeOH:95/5)=0.33

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=59/41 ratio: 8.55-8.45 (m, 1H),7.60-7.50 (t, 1H), 7.30-7.10 (m, 6H), 3.90-3.70 (m, 2H, conformer A),3.40-3.30 (t, 2H, conformer B), 3.15 (s, 3H, conformer B), 2.90 (s, 3H,conformer A), 2.85-2.75 (t, 2H, conformer A), 2.60-2.50 (t, 2H,conformer B), 2.25-2.15 (2s, 3H, conformer A+B)

Example 213 2-Fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 2-fluorobenzoyl chloride (59 mg, 0.37 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 28mg of 2-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as abrown oil (Yield: 32%).

LCMS (RT): 3.00 min; MS (ES+) gave m/z: 283

Rf (DCM/MeOH:95/5)=0.33

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=57/43 ratio: 8.55-8.45 (m, 1H),7.70-7.60 (t, 1H), 7.45-7.30 (m, 3H), 7.25-7.05 (m, 3H), 3.88-3.75 (t,2H, conformer A), 3.55-3.45 (t, 2H, conformer B), 3.20 (s, 3H, conformerB)-3.00 (s, 3H, conformer A), 2.90-2.80 (t, 2H, conformer A), 2.70-2.60(t, 2H, conformer B).

Example 214 N,4-Dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 4-methylbenzoyl chloride (58 mg, 0.37 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 31mg of N,4-dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brownoil (Yield: 36%).

Rf (DCM/MeOH:95/5)=0.35

LCMS (RT): 3.28 min; MS (ES+) gave m/z: 279

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=58/42 ratio: 8.55-8.45 (m, 1H),7.70-7.60 (t, 1H), 7.40-7.15 (m, 6H), 3.85-3.70 (m, 2H, conformer A),3.65-3.50 (m, 2H, conformer B), 3.10 (s, 3H), 2.92-2.80 (m, 2H,conformer A), 2.78-2.60 (m, 2H, conformer B), 2.35 (s, 3H)

Example 215 N,3-Dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 3-methylbenzoyl chloride (58 mg, 0.37 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 25mg of N,3-dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a yellowpale oil (Yield: 29%).

LCMS (RT): 3.37 min; MS (ES+) gave m/z: 279

Rf (DCM/MeOH: 95/5)=0.36

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=55/45 ratio: 8.55-8.45 (m, 1H),7.60-7.50 (t, 1H), 7.35-7.10 (m, 6H), 3.80-3.70 (m, 2H, conformer A),3.55-3.40 (m, 2H, conformer B), 3.10-3.00 (s, 3H, conformer A+B),2.80-2.70 (m, 2H, conformer A), 2.65-2.50 (m, 2H, conformer B), 2.25 (s,3H)

Example 216 2-Methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 2-methoxybenzoyl chloride (69 mg, 0.41 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 71mg of 2-methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as agreen-brown oil (Yield: 77%).

LCMS (RT): 3.08 min; MS (ES+) gave m/z: 295

Rf (DCM/MeOH: 95/5)=0.39

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=50/50 ratio: 8.55-8.45 (m, 1H),7.68-7.58 (t, 1H), 7.42-7.18 (m, 4H), 7.00-6.88 (m, 2H), 3.90-3.80 (m,4H), 3.50-3.40 (m, 1H), 3.20 (s, 3H, conformer A), 2.95 (s, 3H,conformer B), 2.90-2.80 (t, 2H, conformer A), 2.70-2.60 (t, 2H,conformer B).

Example 2172,3-Difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 2,3-difluorobenzoyl chloride (72 mg, 0.41 mmol). Thecrude residue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 67mg of 2,3-difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as abrown oil (Yield: 71%).

LCMS (RT): 3.32 min; MS (ES+) gave m/z: 301

Rf (DCM/MeOH:95/5)=0.28

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=60/40 ratio: 8.55-8.45 (m, 1H),7.60-7.50 (t, 1H), 7.35-7.20 (m, 1H), 7.20-7.00 (m, 4H), 3.80-3.70 (t,2H, conformer A), 3.50-3.40 (t, 2H, conformer B), 3.15 (s, 3H, conformerB), 2.95 (s, 3H, conformer A), 2.80-2.70 (t, 2H, conformer A), 2.65-2.50(t, 2H, conformer B).

Example 2182,6-Dichloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 2,6-dichlorobenzoyl chloride (85 mg, 0.41 mmol). Thecrude residue was purified over silicagel chromatography (prepacked 10 gsilicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 47mg of 2,6-dichloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as abrown oil (Yield: 45%).

Rf (DCM/MeOH: 95/5)=0.38

LCMS (RT): 3.53 min; MS (ES+) gave m/z: 333

¹H-NMR (CDCl₃), δ (ppm) 2 conformers A/B=71/29 ratio: 8.55-8.45 (m, 1H),7.60-7.50 (t, 1H), 7.30-7.10 (m, 5H), 3.80-3.70 (t, 2H, conformer A),3.40-3.30 (t, 2H, conformer B), 3.15 (s, 3H, conformer B), 2.90 (s, 3H,conformer A), 2.85-2.75 (t, 2H, conformer A), 2.70-2.60 (t, 2H,conformer B).

Example 219N,3,5-Trimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)isoxazole-4-sulfonamide

The title compound was prepared in accordance with the general method ofExample 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg,0.31 mmol) and 3,5-dimethylisoxazole-4-sulfonyl chloride (79 mg, 0.41mmol). The crude residue was purified over silicagel chromatography(prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 aseluent) to afford 17 mg ofN,3,5-trimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)isoxazole-4-sulfonamide asa brown oil (Yield: 17%).

Rf (DCM/MeOH:95/5)=0.42

LCMS (RT): 3.47 min; MS (ES+) gave m/z: 320

¹H-NMR (CDCl₃), δ (ppm): 8.60-8.50 (d, 1H), 7.70-7.60 (t, 1H), 7.40-7.30(d, 1H), 7.30-7.15 (m, 1H), 3.50-3.40 (t, 2H), 2.93 (s, 3H), 2.80-2.70(t, 2H), 2.65 (s, 3H), 2.40 (s, 3H)

Example 220 N-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]thiazol-2-amine 220(A)4-(Pyridin-2-yl)but-3-yn-1-amine

To a solution of 2-(4-(Pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione(compound 3(B), 6.81 g, 34 mmol) in ethanol (20 mL, 0.3M) was added 6.6mL of hydrazine hydrate 25%. The reaction mixture was heated 4 hoursat50° C. The awaited product was formed and the starting material wascompletely consumed. The reaction mixture was washed twice with NaHCO₃saturated, and the organic layer was dried, filtrated and concentrated.

Purification by flash chromatography reverse phase (C18 column, pack 35g, with H₂O/Acetonitrile:95/5 as eluent), to afford 814 mg of4-(pyridin-2-yl)but-3-yn-1-amine (Yield: 82%) as yellow solid.

220(B) N-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]thiazol-2-amine

4-(pyridin-2-yl)but-3-yn-1-amine (640 mg, 4.40 mmol),2-chlorobenzo[d]thiazole (373 mg, 2.2 mmol) and DIEA (452 μL, 2.64 mmol)wre poured into DMF (2.2 mL) and the resulting solution was heated twodays at 120° C. The solvent was removed under reduce pressure and thecrude product was purified over silicagel chromatography (prepacked 25 gsilicagel column, Cyclohexane/AcOEt:70/30 as eluent) to afford 582 mg ofN-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazol-2-amine (Yield: 95%) as abrownish oil.

LCMS (RT): 3.09 min; MS (ES+) gave m/z: 280

Rf (Cyclohexane/AcOEt:70/30)=0.30

Example 2211-Methyl-3-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d]imidazol-2(3H)-one221(A) 2-(5-Chloropent-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 190(F), from 2-bromopyridine (948 mg, 6.0 mmol) and5-chloropent-1-yne (620 mg, 6.0 mmol). The crude residue was purifiedover silicagel chromatography (prepacked 25 g silicagel column,Cyclohexane/AcOEt: from 100/0 to 80/20 as eluent) to afford 655 mg of2-(5-chloropent-1-ynyl)pyridine as a yellow oil (Yield: 61%).

LCMS (RT): 3.56 min; MS (ES+) gave m/z: 180

Rf (Cyclohexane/AcOEt:80/20)=0.30

221(B)1-Methyl-3-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d]imidazol-2(3H)-one

2-(5-chloropent-1-ynyl)pyridine (59 mg, 0.33 mmol),1-methyl-1H-benzo[d]imidazol-2(3H)-one (44 mg, 0.3 mmol) and K₂CO₃ (70mg, 0.51 mmol) were poured into DMF (0.45 mL) and the resulting mixturewas heated at 50° C. overnight. The mixture was purified over silicagelchromatography (prepacked 25 g silicagel column, DCM 100% as eluent) toafford 40 mg of1-methyl-3-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d]imidazol-2(3H)-oneas a yellow oil (Yield: 43%).

LCMS (RT): 3.29 min; MS (ES+) gave m/z: 292

¹H-NMR (CDCl₃), δ (ppm): 8.55-8.54 (d, 1H), 7.63-7.60 (m, 1H), 7.37-7.35(d, 1H), 7.21-7.18 (m, 1H), 7.12-7.07 (m, 3H), 6.97-6.95 (m, 1H),4.07-4.04 (t, 2H), 3.41 (s, 3H), 2.54-2.51 (t, 2H), 2.13-2.07 (m, 2H).

Example 2222-(4-(4,5-Dimethylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

222(A) 2-Bromo-4,5-dimethylthiazole

Bromine (272 μL, 5.30 mmol) was added dropwise to a solution of4,5-dimethylthiazole (200 mg, 1.77 mmol) in chloroform (5 mL) at 0° C.and the reaction mixture was stirred for 5 hours at room temperature.Sodium thiosulfate solution was added to the reaction mixture and theaqueous phase was extracted with DCM. The organic phase was washed withwater, brine, dried over Na₂SO₄, filtered and concentrated. The cruderesidue was purified by flash chromatography (pentane/Et₂O 95:5) toyield 250 mg (1.30 mmol, 74%) of 2-bromo-4,5-dimethylthiazole.

222(B)2-(4-(4,5-Dimethylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-4,5-dimethylthiazole (100 mg, 0.52 mmol) and2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (89 mg, 0.52 mmol, Example109(D)). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 25 mg (89 mmol, 17%) of2-(4-(4,5-dimethylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole asa yellow solid (M.P.=96-98° C.).

LCMS (RT): 4.50 min; MS (ES+) gave m/z: 283.1

Rf (cyclohexane/AcOEt 7:3)=0.3.

¹H-NMR (CDCl₃), δ (ppm): 2.31 (s, 3H), 2.34 (s, 3H), 3.29 (t, J=7.5,2H), 4.96 (t, J=7.5, 2H), 7.39 (dd, J=3.0 and 6.3, 2H), 7.86 (dd, J=3.0and 6.3, 2H).

Example 2236-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine223(A)Trimethyl(4-(oxiran-2-yl)but-1-ynyl)silane

To a stirred solution of trimethyl(prop-1-ynyl)silane (3 g, 26.7 mmol)in dry THF (100 mL) cooled at −72° C., was added drop by drop 2.5 NnBuLi in hexane solution (10.5 mL, 26.2 mmol). The resulting mixture wasstirred at −75° C. for 1 h30. Then 2-(chloromethyl)oxirane (2.42 g, 26.2mmol) in dry THF (2 mL) was slowly added. The resulting mixture wasstirred at −72° C. for 1 h30, then warmed up to room temperature for anadditional 1 h. The reaction mixture was quenched with water andextracted with diethyl ether. The organic phase was dried over MgSO₄,filtered and concentrated under reduced pressure to afford 4.50 gtrimethyl(4-(oxiran-2-yl)but-1-ynyl)silane (Yield: 100%) as a yellow oilwhich was used in the next step without further purification.

Rf (Cyclohenaxe/AcOEt:70/30)=0.61

223 (B) 1-Bromo-6-(trimethylsilyl)hex-5-yn-2-ol

To a stirred solution of trimethyl(4-(oxiran-2-yl)but-1-ynyl)silane (4.5g, 27 mmol) in THF (90 mL) containing acetic acid (4.81 g, 80.21 mmol),was added at 0° C. ahydrous LiBr (3.71 g, 42.78 mmol). The reactionmixture was left stiffing overnight at room temperature. The reactionwas quenched with saturated NaCl and extracted with Et₂O. The organicphase was washed once with a solution of 1M K₂CO₃ saturated with NaCl,brine, dried over MgSO₄, filtered and concentrated. The crude residuewas purified over silicagel chromatography (prepacked 70 g silicagelcolumn, from Cyclohxane 100% to DCM 100% as eluent) to afford 2.5 g of1-bromo-6-(trimethylsilyl)hex-5-yn-2-ol (Yield: 38%) as a yellow oil.

¹H-NMR (CDCl₃), δ (ppm): 3.95-3.80 (m, 1H), 3.65-3.30 (m, 2H), 2.38-2.20(m, 3H), 1.75-1.65 (m, 2H), 0.05 (s, 9H)

223(C) 1-Bromo-6-(trimethylsilyl)hex-5-yn-2-one

1-bromo-6-(trimethylsilyl)hex-5-yn-2-ol (2.85 g, 10 mmol) were dissolvedin acetone (13 mL). Preparation of Jone's reagent: 1.2 gr of CrO₃ aredissolved in conc. H₂SO₄ (1.2 mL). 5 mL of H₂O were added. The resultingmixture was stirred 10 min until CrO₃ was completely dissolved to give ared orange solution.

The Jone's reagent was slowly added to the solution of1-bromo-6-(trimethylsilyl)hex-5-yn-2-ol in acetone; the color getsgreen, green-brown then dark brown. Jone's reagent was added until thedark brown color remains. The reaction was monitored by TLC (DCM 100%),Rf=0.75

Isopropanol was added to quench the excess of Jone's reagent, and theproduct was extracted with DCM. The organic phases were washed twicewith water, dried over MgSO₄, filtered and concentrated under reducedpressure to afford 1.85 g which was a mixture of1-chloro-6-(trimethylsilyl)hex-5-yn-2-one and1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (in 1/1 ratio) as a yellow oil(Yield: 75%). The product was immediately used in next step withoutfurther purification.

Rf (DCM: 100%)=0.75

¹H-NMR (CDCl₃), δ (ppm) mixture of α-chloroketone/α-bromoketone 1/1ratio: 4.04 (s, 2H, α-chloroketone), 3.84 (s, 2H, α-bromoketone),2.90-2.70 (m, 2H, α-chloroketone+α-bromoketone), 2.50-2.40 (t,α-chloroketone+α-bromoketone), 0.03 (s, 9H,α-chloroketone+α-bromoketone).

223(D) 6-Fluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine

To a stirred solution of 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (2.50g, 10.11 mmol) in EtOH (8 mL) was added potassium carbonate (350 mg,2.53 mmol) and 5-fluoropyridin-2-amine (567 mg, 5.06 mmol). The mixturewas heated at 80° C. overnight. The mixture was concentrated, theresidue was dissolved in EtOAc, and the organic layer was washed withbrine, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified over silicagel chromatography(prepacked 70 g silicagel column, from DCM/MeOH: 100/0 to 96/4 aseluent) to afford 400 mg of6-fluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:30%) as an orange-brown solid.

Rf (DCM/MeOH:95/5)=0.38

LCMS (RT): 3.05 min; MS (ES+) gave m/z: 261

223(E) 2-(But-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(D), the conversion of6-fluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (400mg, 1.53 mmol) afforded 220 mg of2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (Yield: 76%) asyellow-oil.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, DCM/MeOH: 98/2 as eluent).

LCMS (RT): 0.63-1.61 min; MS (ES+) gave m/z: 189

Rf (DCM/MeOH:95/5)=0.37

223(F)6-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 190(F), from 2-bromo-6-(fluoromethyl)pyridine (220 mg, 1.10 mol)and 2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (220 mg, 1.14 mmol).The crude residue was purified over C18 chromatography (prepacked 35 gsilicagel column, H₂O/CH₃CN: from 95/5 to 55/45 as eluent) to afford 155mg of6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine(Yield: 46%) as a white powder (Mp=140-141.8° C.).

LCMS (RT): 2.49 min; MS (ES+) gave m/z: 298

Rf (DCM/MeOH: 95/5)=0.32

¹H-NMR (CDCl₃), δ (ppm): 8.65-8.60 (m, 1H), 7.80-7.70 (m, 2H), 7.50-7.40(m, 1H, 7.38-7.30 (m, 1H), 7.25-7.10 (m, 1H), 5.41-2.25 (d, 2H),2.93-2.88 (m, 2H), 2.80-2.75 (m, 2H).

Example 2246-Fluoro-2-(4-(2-(fluoromethyl)thiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine224(A) 4-Bromothiazole-2-carbaldehyde

To a solution of 2,4-dibromothiazole (730 mg, 3.0 mmol) in anhydrousEt₂O (15 mL) was added at −78° C., nBuLi 2.5M in hexane (1.4 mL, 3.6mmol), and the resulting solution was stirred at the same temperaturefor 30 min. DMF (0.46 mL, 6 mmol) was added at −78° C. and, after beingstirred at −78° C. for 30 min, the reaction mixture was slowly warmed upto room temperature over a period of 2 h. Cyclohexane was added and theresulting mixture was passed through a short silica gel cake elutingwith Cyclohexane/AcOEt 70/30 to give the 462 mg of4-bromothiazole-2-carbaldehyde (Yield: 80%) which was used directly inthe next step.

224(B) (4-Bromothiazol-2-yl)methanol

To a solution of 4-bromothiazole-2-carbaldehyde (462 mg, 2.40 mmol) inmethanol (24 mL) was added at room temperature sodium borohydride (140mg, 3.60 mmol), and the resulting mixture was stirred 1 h at the sametemperature. EtOAc (3 mL) and cyclohexane (6 mL) were added, and themixture was passed through a short silica gel cake and eluting withEtOAc 100% to give 390 mg of (4-bromothiazol-2-yl)methanol (Yield: 83%)as a beige oil which slowly cristalize.

LCMS (RT): 2.43 min; MS (ES+) gave m/z: 194

224(C) 4-Bromo-2-(fluoromethyl)thiazole

A solution of (4-bromothiazol-2-yl)methanol (390 mg, 2.0 mmol) in 7 mLof dry DCM, was added dropwise −78° C. to a solution at of DAST (0.738mL, 6.0 mmol) in dry DCM (5.5 mL). The reaction mixture was stirred 1 hat −78° C. then 1 h at room temperature. The reaction was quenched withwater, and the organic layer extracted with DCM, dried over MgSO₄,filtrated and evaporated.

The crude residue was purified over silicagel chromatography (prepacked25 g silicagel column, Cyclohexane/AcOEt:95/5 as eluent) to afford 84 mgof 4-bromo-2-(fluoromethyl)thiazole as a yellow oil (Yield: 21%).

LCMS (RT): 3.38 min; MS (ES+) gave m/z: 197

224(D)6-Fluoro-2-(4-(2-(fluoromethyl)thiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 190(F), from 4-bromo-2-(fluoromethyl)thiazole (84 mg, 0.43 mmol)and 2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (compound 223(E), 80mg, 0.43 mmol). The crude residue was purified over C18 chromatography(prepacked 35 g silicagel column, H₂O/CH₃CN: from 100/0 to 80/20 aseluent) to afford 65 mg of6-fluoro-2-(4-(2-(fluoromethyl)thiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine(Yield: 47%) as a beige powder (Mp=82-84° C.).

LCMS (RT): 2.54 min; MS (ES+) gave m/z: 304

Rf (DCM/MeOH:95/5)=0.32

¹H-NMR (CDCl₃), δ (ppm): 8.06-8.01 (t, 1H), 7.72-7.65 (m, 1H), 7.62-7.44(m, 2H), 7.16-7.10 (t, 1H), 5.64-5.54 (d, 2H), 3.15-3.12 (t, 2H),2.92-2.89 (t, 2H)

Example 2258-Bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine225(A) 8-Bromo-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 223(D), from 3-bromopyridin-2-amine (280 mg, 1.60 mmol) and1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (compound 223(C), 870 mg, 3.5mmol). The crude residue was purified over silicagel chromatography(prepacked 25 g silicagel column, DCM/MeOH: from 100/0 to 98/2 aseluent) to afford 315 mg of8-bromo-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield:61%) as a yellow oil.

225(B) 8-Bromo-2-(but-3-ynyl)-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(D), the conversion of8-bromo-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (315 mg,0.98 mmol) afforded 241 mg of8-bromo-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 98%) asyellow-oil.

LCMS (RT): 0.76 min; MS (ES+) gave m/z: 250

225(C)8-Bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 190(F), from 2-bromo-6-(fluoromethyl)pyridine (180 mg, 0.97mmol) and 8-bromo-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (242 mg, 0.97mmol). The crude residue was purified over silicagel chromatography(prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 100/0 to 60/40as eluent) to afford 36 mg of8-bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine(Yield: 10%) as a yellow oil.

LCMS (RT): 2.58 min; MS (ES+) gave m/z: 358

¹H-NMR (CDCl₃), δ (ppm): 8.08-8.04 (d, 1H), 7.73-7.67 (t, 1H), 7.62 (s,1H), 7.45-7.41 (d, 1H), 7.41-7.37 (d, 1H), 7.34-7.31 (d, 1H), 6.67-6.62(t, 1H), 3.15-3.25 (t, 2H), 3.00-2.90 (t, 2H)

Example 2268-(Benzyloxy)-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

226(A)8-(Benzyloxy)-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 223(D), from 3-(benzyloxy)pyridin-2-amine (274 mg, 1.37 mmol)and 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (compound 223(C), 750 mg,3.0 mmol). The crude residue was purified over silicagel chromatography(prepacked 25 g silicagel column, DCM/MeOH: from 98/2 to 95/5 as eluent)to afford 331 mg of8-(benzyloxy)-2-(4-(trimethylsilyl)but-3-ynyl)H-imidazo[1,2-a]pyridine(Yield: 69%) as a yellow oil.

LCMS (RT): 3.68 min; MS (ES+) gave m/z: 349

226(B) 8-(Benzyloxy)-2-(but-3-ynyl)-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(D), the conversion of8-bromo-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (331 mg,0.95 mmol) afforded 183 mg of8-(benzyloxy)-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 70%) asyellow-oil.

LCMS (RT): 2.58 min; MS (ES+) gave m/z: 277

226(C)8-(Benzyloxy)-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 190(F), from 2-bromo-6-(fluoromethyl)pyridine (82 mg, 0.43 mmol)and 8-(benzyloxy)-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (119 mg, 0.43mmol). The crude residue was purified over silicagel chromatography(prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 100/0 to 60/40as eluent) to afford 10 mg of8-(benzyloxy)-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine(Yield: 6%) beige solid (Mp=92-94° C.)

LCMS (RT): 3.01 min; MS (ES+) gave m/z: 386

¹H-NMR (CDCl₃), δ (ppm): 7.75-7.65 (m, 2H), 7.55-7.30 (m, 8H), 6.60-6.50(t, 1H), 6.45-6.35 (d, 1H), 5.55-5.40 (d, 2H), 5.35 (s, 2H), 3.19-3.14(t, 2H), 2.96-2.91 (t, 2H)

Example 2272-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-8-phenyl-imidazo[1,2-a]pyridine

To a solution of8-bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine(compound 171(C), 301 mg, 0.84 mmol) and phenylboronic acid (50 mg, 1.3mmol) in degazed DME (4.2 mL) was added 1.32 mL of a solution of K₃PO₄2M (degazed before use). After stiffing at room temperature for 5 minunder N₂, Pd(PPh₃)₄ (190 mg, 0.17 mmol) was added in one portion. Theresulting mixture was heated at 80° C. for 4 h. The Mixture was cooleddown to room temperature and diluted in AcOEt. The organic layer waswashed twice with saturated NaCl, dried over magnesium sulfate, filteredand concentrated. The crude product was purified over silicagelchromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt:60/40as eluent) to afford 137 mg of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-8-phenyl-imidazo[1,2-a]pyridine_(Yield:46%) as a yellow oil.

LCMS (RT): 3.19 min; MS (ES+) gave m/z: 356

¹H-NMR (CDCl₃), δ (ppm): 8.80-8.40 (d, 1H), 8.40-8.00 (m, 2H), 7.72-7.66(t, 1H), 7.57 (s, 1H), 7.51-7.23 (m, 6H), 6.87-6.81 (t, 1H), 5.52-5.41(d, 2H), 3.19-3.16 (t, 2H), 2.96-2.93 (t, 2H)

Example 2286,8-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine228(A)6,8-Difluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 223(D), from 3,5-difluoropyridin-2-amine (492 mg, 3.78 mmol) and1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (compound 223(C), 1.87 mg, 7.56mmol). The crude residue was purified over silicagel chromatography(prepacked 25 g silicagel column, from DCM/Cyclohexane:70/30 toDCM/MeOH: 95/5 as eluent) to afford 517 mg of6,8-difluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine(Yield: 49%) as a brown oil.

LCMS (RT): 4.43 min; MS (ES+) gave m/z: 279

¹H-NMR (CDCl₃), δ (ppm): 7.80 (s, 1H), 7.45 (d, 1H), 7.81-7.72 (t, 1H),3.00-2.90 (t, 2H), 2.65-2.50 (t, 2H), 0.05 (s, 9H)

228(B) 2-(But-3-ynyl)-6,8-difluoro-imidazo[1,2-a]pyridine

According to the protocol described in Example 38(D), the conversion of6,8-difluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine(517 mg, 1.86 mmol) afforded 363 mg of2-(but-3-ynyl)-6,8-difluoro-imidazo[1,2-a]pyridine (Yield: 95%) asyellow-oil.

LCMS (RT): 2.55 min; MS (ES+) gave m/z: 207

¹H-NMR (CDCl₃), δ (ppm): 7.80 (s, 1H), 7.50 (s, 1H), 6.84-6.70 (t, 1H),3.00-2.90 (t, 2H), 2.65-2.50 (t, 2H), 1.90 (s, 1H)

228(C)6,8-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

In a dry flask were added CuI (16.9 mg, 0.08 mmol) and TEA (5 mL)followed by 2-iodopyridine (363 mg, 1.77 mmol) and Pd(PPh₃)₂Cl₂ (82 mg,0.088 mmol). A yellow suspension was obtained after 5 min of stiffing.To this suspension was added2-(but-3-ynyl)-6,8-difluoro-imidazo[1,2-a]pyridine (365 mg, 1.77 mmol)and the reaction mixture turns to black. After 4 h at room temperature,the TEA was evaporated; the crude product was dissolved in DCM andfiltered over celite. The organic layer was washed with aqueous 2Nammonia, brine, dried over MgSO₄, and the solvent was evaporated to givea brown solid (588 mg). The crude product was purified over silicagelchromatography (prepacked 25 g silicagel column, DCM/AcOEt: form 100/0to 95/5 as eluent) to afford 293 mg of6,8-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine. Asecond purification over C18 was performed using H₂O/CH₃CN: from 80/20to 70/30 as eluent) to afford 146 mg of the title compound as a brownishpowder contaminated by PPh₃O. The solid was dissolved in aqueous 0.1NHCl (20 mL) 1 and the aqueous phase was washed twice with DCM (3*10 mL).The aqueous layer was neutralised with sat NaHCO₃ and extracted in ether(3*10 mL). The organic layer was washed with water (10 mL), brine (10mL), and dried over MgSO₄. Evaporation of the solvent afford 124 mg of6,8-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine(Yield: 25%) as a white solid (Mp=130-131° C.).

LCMS (RT): 2.67 min; MS (ES+) gave m/z: 284

Rf (DCM/MeOH: 96/4)=0.23

¹H-NMR (CDCl₃), δ (ppm): 8.50-8.40 (d, 1H), 7.90-7.80 (m, 1H), 7.60-7.50(m, 2H), 7.35-7.25 (d, 1H), 7.18-7.08 (m, 1H), 6.86-6.72 (t, 1H),3.15-3.00 (t, 2H), 2.90-2.80 (t, 2H)

Example 2292-(4-(4-Methylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole 229(A)2-Bromo-4-methylthiazole

A solution of sodium nitrite (378 mg, 5.47 mmol) in water (2.25 mL) wasadded to a mixture of 4-methyl-thiazol-2-ylamine (500 mg, 4.38 mmol),phosphoric acid (4.50 mL) and nitric acid (2.25 mL) at −10° C. Afterstirring the reaction mixture for 45 min. at −10° C., it was poured ontoa solution of CuSO₄ (1.37 g, 5.47 mmol) and sodium bromide (1.13 g, 10.9mmol). Then the solution was stirred for 30 min. at room temperature,for 3 hours at 50° C. and was neutralized with a solution of NaOH (2M).The aqueous phase was extracted with DCM. The organic phase was washedwith water, brine, dried over Na₂SO₄, filtered and concentrated. Thecrude residue was purified by flash chromatography (pentane/ether 95:5)to yield 250 mg (1.40 mmol, 32%) of 2-bromo-4-methylthiazole as anorange oil.

LCMS (RT): 3.62 min; MS (ES+) gave m/z: 179.1.

229(B) 2-(4-(4-Methylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-4-methylthiazole (100 mg, 0.56 mmol) and2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (96 mg, 0.56 mmol, Example109(D)). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 40 mg (0.15 mmol, 27%) of2-(4-(4-methylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as awhite solid (M.P.=78-80° C.).

LCMS (RT): 4.05 min; MS (ES+) gave m/z: 269.1

Rf (cyclohexane/AcOEt 7:3)=0.3.

¹H-NMR (CDCl₃), δ (ppm): 2.44 (s, 3H), 3.31 (t, J=7.5, 2H), 4.98 (t,J=7.5, 2H), 6.85 (s, 1H), 7.39 (dd, J=3.3 and 6.3, 2H), 7.87 (dd, J=3.3and 6.3, 2H).

Example 230 (3-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole 230(A)3-Fluoro-2-iodopyridine

To a solution of 2-chloro-3-fluoropyridine (400 mg, 3 mmol) in dioxane(6 mL, 0.5M) was added in one portion chlorotrimethylsilane (652 mg, 6mmol) and sodium iodide (2.20 g, 15 mmol). The resulting mixture wasstirred at 80° C. overnight. The reaction mixture was concentrated toafford 660 mg of 3-fluoro-2-iodopyridine (Yield: 98%) as a yellow oilwhich was used in the next step without further purification.

230(B) (3-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole

In a dry reaction tube containing in suspension copper iodide (28 mg,0.148 mol) and triethylamine (8.30 mL, 59.20 mmol), were added3-fluoro-2-iodopyridine (660 mg, 2.96 mmol) and Pd(PPh₃)₂Cl₂ (104 mg,0.148 mmol) under N₂. A yellow suspension was obtained. After a 5minutes of stirring at room temperature, was added a solution2-(But-3-ynyl)benzo[d]oxazole (compound 8(A), 510 mg, 3 mmol) intriethylamine (0.2 mL) under N₂. Immediately the color of the reactionturns to black. The mixture was stirred at room temperature for 30 minand heated at 50° C. overnight under N₂. Triethylamine was removed underreduce pressure and the crude product was purified by flashchromatography (Prepacked column 50 g, Cyclohexane/AcOEt:60/40 aseluent) following by C18 chromatography (Prepacked column 15 g,H₂O/CH₃CN: from 80/20 to 40/600 as eluent) to afford 120 mg of2-(4-(3-fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole (Yield: 15%) aswhite powder (Mp=86-88° C.).

LCMS (RT): 4.06 min; MS (ES+) gave m/z: 267

¹H-NMR (CDCl₃), δ (ppm): 8.39-8.36 (m, 1H), 7.73-7.68 (m, 1H), 7.53-7.49(m, 1H), 7.42-7.38 (m, 1H), 7.35-7.30 (m, 2H), 7.27-7.22 (m, 1H),3.35-3.32 (t, 2H), 3.15-3.12 (t, 2H)

Example 231 2-(4-(2-Methyl-1H-imidazol-4-yl)but-3-ynyl)benzo[d]oxazole231(A) Ethyl 4-iodo-2-methyl-1H-imidazole-1-carboxylate

To a solution of 4-iodo-2-methyl-1H-imidazole (162 mg, 0.78 mmol) in THF(2.6 mL, 0.3M) containing DIEA (0.33 mL, 1.95 mmol) and DMAP (47 mg,0.039 mmol), cooled in a ice bath at 0° C., was added a solution ofEthyl chloroformate (211 mg, 1.95 mmol) in THF (2 mL, 1M). The reactionmixture was heated at 50° C. for 48 h and then concentrated. The residuewas dissolved in DCM and the organic layer was washed with saturatedNaCl, dried over magnesium sulfate, filtered and evaporated. The crudeproduct was purified by flash chromatography (Prepacked column 10 g,DCM/MeOH: 97/3 as eluent) to afford 208 mg of ethyl4-iodo-2-methyl-1H-imidazole-1-carboxylate (95%) as colorless oil.

LCMS (RT): 3.69 min; MS (ES+) gave m/z: 281

231(B) Ethyl4-(4-(benzo[d]oxazol-2-yl)but-1-ynyl)-2-methyl-1H-imidazole-1-carboxylate

According to the general protocol for Sonogashira coupling described inExample 38(E), the conversion of ethyl4-iodo-2-methyl-1H-imidazole-1-carboxylate (686 mg, 2.45 mmol) afforded369 mg of ethyl4-(4-(benzo[d]oxazol-2-yl)but-1-ynyl)-2-methyl-1H-imidazole-1-carboxylate(Yield: 46%) as a beige powder.

The crude residue was purified over silicagel chromatography (prepacked25 g silicagel column, Cyclohexane/AcOEt:50/50 as eluent)

LCMS (RT): 4.18 min; MS (ES+) gave m/z: 324

Rf (Cyclohexane/AcOEt:50/50)=0.35

231(C) 2-(4-(2-Methyl-1H-imidazol-4-yl)but-3-ynyl)benzo[d]oxazole

A solution 2.0 N of NaOH was added dropwise to a solution of ethyl4-(4-(benzo[d]oxazol-2-yl)but-1-ynyl)-2-methyl-1H-imidazole-1-carboxylate(369 mg, 1.14 mmol) in EtOH (5.7 mL) and the mixture was heated at 80°C. overnight. Ethanol was concentrated under reduce pressure, then waterwas added and the aqueous layer was extracted with DCM. The recombinedorganics layers were washed once with saturated NaCl, dried over MgSO4,filtered and concentrated.

The crude residue was purified over silicagel chromatography (prepacked25 g silicagel column, DCM/MeOH:97/3 as eluent) to afford 102 mg of2-(4-(2-methyl-1H-imidazol-4-yl)but-3-ynyl)benzo[d]oxazole (Yield: 35%)as a beige powder (Mp=152-154° C.).

LCMS (RT): 2.46 min; MS (ES+) gave m/z: 252

Rf (DCM/MeOH:95/5)=0.4

¹H-NMR (CDCl₃), δ (ppm): 7.70-7.67 (m, 1H), 7.52-7.48 (m, 1H), 7.34-7.27(m, 2H), 7.03 (s, 1H), 3.25-3.22 (t, 2H), 3.03-3.00 (t, 2H), 2.38 (s,3H)

Example 2325-(6-(Fluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)pent-4-ynamide 232(A)(4-Fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester

The title compound was prepared in accordance with the general method ofExample 34(B), from N-(4-fluorophenyl)pent-4-ynamide (400 mg, 2.09 mmol,34(A)). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 505 mg (1.73 mmol, 83%) of(4-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester as acolourless oil.

LCMS (RT): 4.72 min; MS (ES+) gave m/z: 192.1.

232(B)[5-(6-Fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-phenyl)-carbamicacid tert-butyl ester

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)pyridine (180 mg, 0.95 mmol,Example 190(E)) and (4-fluoro-phenyl)-pent-4-ynoyl-carbamic acidtert-butyl ester (276 mg, 0.95 mmol). Reaction time: 3 hours. The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 4:1) toyield 300 mg (0.75 mmol, 79%) of[5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-phenyl)-carbamicacid tert-butyl ester as a white solid.

LCMS (RT): 4.90 min; MS (ES+) gave m/z: 301.1.

Rf (cyclohexane/AcOEt 4:1)=0.2.

232(C) 5-(6-(Fluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)pent-4-ynamide

The title compound was prepared in accordance with the general method ofExample 34(D), from[5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-phenyl)-carbamicacid tert-butyl ester (300 mg, 0.75 mmol). After the work-up, the cruderesidue was washed with diisopropyl ether to yield 120 mg (0.40 mmol,53%) of5-(6-(fluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)pent-4-ynamide as abeige powder (M.P.=110° C.).

LCMS (RT): 3.77 min; MS (ES+) gave m/z: 301.1.

¹H-NMR (CDCl₃), δ (ppm): 2.68 (t, J=6.9, 2H), 2.88 (t, J=6.9, 2H), 5.46(d, J=46.8, 2H), 6.95-7.04 (2H), 7.32 (d, J=8.1, 1H), 7.40 (d, J=7.5,1H), 7.43-7.52 (3H), 7.67-7.74 (m, 1H).

Example 2332-(4-(1,2-Dimethyl-1H-imidazol-4-yl)but-3-ynyl)benzo[d]oxazole

In a dry microwave tube were placed in suspension CuI (19 mg, 0.1 mmol)and triethylamine (3.79 mL, 27 mmol). Then under nitrogen atmosphere,were added the 4-bromo-1,2-dimethyl-1H-imidazole (350 mg, 2.0 mmol),PdCl₂(PPh₃)₂ (70 mg, 0.1 mmol), and triphenyl phosphine polymerbound(130 mg, 0.4 mmol). The suspension was stirred at room temperature forfew minutes, finally the 2-(But-3-ynyl)benzo[d]oxazole (compound 43(A),340 mg, 2.0 mmol) in 0.4 mL of DMF was added, and the reaction mixtureis stirred at room temperature for 30 min. The reaction mixture wasstirred and heated under micro wave irradiation for 25 min at 120° C.After filtering to remove triphenyl phosphine polymerbound., thetriethylamine was concentrated under reduce pressure and the residue wasdissolved in DCM. The organic layer was washed with saturated NaHCO₃,H₂O and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated.

Purification over C18 chromatography (prepacked 35 g C18 column,H₂O/CH₃CN: from 100/0 to 60/40 as eluent) to afford 28 mg of2-(4-(1,2-dimethyl-1H-imidazol-4-yl)but-3-ynyl)benzo[d]oxazole (Yield:5%) as a beige powder (Mp=117-119° C.).

LCMS (RT): 2.53 min; MS (ES+) gave m/z: 266

¹H-NMR (CDCl₃), δ (ppm): 7.69-7.67 (m, 1H), 7.50-7.48 (m, 1H), 7.32-7.27(m, 2H), 6.89 (s, 1H), 3.54 (s, 3H), 3.28-3.22 (t, 2H), 3.04-2.98 (t,2H), 2.36 (s, 3H)

Example 234 2-(4-(Pyridin-2-yl)but-3-ynyflisoindolin-1-one 234(A)Methyl-2-(bromomethyl)benzoate

A solution of methyl-2-methylbenzoate (250 mg, 1.66 mmol), NBS (296 mg,1.66 mmol) and dibenzoylperoxide (403 mg, 1.66 mmol) was stirred underreflux for one day. After purification by flash chromatography, 350 mg(1.53 mmol, 92%) of methyl-2-(bromomethyl)benzoate were obtained as acolorless oil.

234(B) 2-(4-(Trimethylsilyl)but-3-ynyl)isoindolin-1-one

4-Trimethylsilyl)but-3-yn-1-amine (215 mg, 1.52 mmol),methyl-2-(bromomethyl)benzoate (349 mg, 1.52 mmol) and Et₃N (0.42 mL,3.04 mmol) were placed in a microwave tube and heated for 10 min. at100° C. The solvent was evaporated and the crude residue was dissolvedin DCM. The organic phase was washed with water, brine, dried overNa₂SO₄, filtered and concentrated to yield 250 mg (0.97 mmol, 64%) of2-(4-(trimethylsilyl)but-3-ynyl)isoindolin-1-one as a colourless oil.

234(C) 2-(But-3-ynyl)isoindolin-1-one

The title compound was prepared in accordance with the general method ofExample 108(B), from 2-(4-(trimethylsilyl)but-3-ynyl)isoindolin-1-one(250 mg, 0.97 mmol). The crude residue was purified by flashchromatography (cyclohexane/AcOEt 3:2) to yield 85 mg (0.46 mmol, 47%)of 2-(but-3-ynyl)isoindolin-1-one as a colourless oil.

LCMS (RT): 3.03 min; MS (ES+) gave m/z: 186.1.

234(D) 2-(4-(Pyridin-2-yl)but-3-ynyl)isoindolin-1-one

The title compound was prepared in accordance with the general method ofExample 1, from 2-iodopyridine (94 mg, 0.46 mmol) and2-(but-3-ynyl)isoindolin-1-one (85 mg, 0.46 mmol). Reaction conditions:14 hours at room temperature. The crude residue was purified by flashchromatography (cyclohexane/AcOEt 1:1 to 0:1) to yield 45 mg (0.17 mmol,37%) of 2-(4-(pyridin-2-yl)but-3-ynyl)isoindolin-1-one as a white solid(M.P.=94-98° C.).

LCMS (RT): 2.90 min; MS (ES+) gave m/z: 263.2.

Rf (AcOEt)=0.3.

¹H-NMR (CDCl₃), δ (ppm): 2.83 (t, J=6.6, 2H), 3.89 (t, J=6.6, 2H), 4.60(d, J=6.6, 2H), 7.14-7.24 (m, 1H), 7.33 (d, J=7.8, 1H), 7.40-7.55 (3H),7.56-7.67 (m, 1H), 7.84 (d, J=6.9, 1H), 8.48-8.60 (m, 1H).

Example 235 4-(Pyridin-2-yl)but-3-ynyl 2-chlorobenzoate 235(A)4-(Pyridin-2-yl)but-3-yn-1-ol

In a dry microwave tube were placed in suspension CuI (49.5 mg, 0.26mmol) and triethylamine (9.85 mL, 70.20 mmol). Then under nitrogenatmosphere, were added the 2-bromopyridine (822 mg, 5.2 mmol),PdCl₂(PPh₃)₂ (182 mg, 0.26 mmol), and triphenyl phosphine polymerbound(350 mg, 1.0 mmol). The suspension was stirred at room temperature forfew minutes, finally the but-3-yn-1-ol (364 mg, 5.20 mmol) in 0.5 mL ofDMF was added, and the reaction mixture is stirred at room temperaturefor 30 min.

The reaction mixture was stirred and heated under micro wave irradiationfor 10 min at 120° C. After filtering to remove triphenyl phosphinepolymerbound, the triethylamine was concentrated under reduce pressureand the residue was dissolved in DCM. The organic layer was washed withsaturated NaHCO₃, H₂O and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated.

Purification over silicagel chromatography (prepacked 50 g silicagelcolumn, DCM/MeOH: 98/2 as eluent) to afford 620 mg of4-(pyridin-2-yl)but-3-yn-1-ol (Yield: 81%) as a yellow oil.

LCMS (RT): 1.76 min; MS (ES+) gave m/z: 148

235(B) 4-(Pyridin-2-yl)but-3-ynyl 2-chlorobenzoate

To solution of 2-chlorobenzoic acid (330 mg, 2.10 mmol),4-(pyridin-2-yl)but-3-yn-1-ol (310 mg, 2.1 mmol), in DCM (7 mL), wassuccessively added EDCI.HCl (600 mg, 3.2 mmol) and DMAP (13 mg, 0.105mmol). The resulting mixture was then stirred overnight at ambienttemperature. The reaction mixture was concentrated.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn,

Cyclohexane/AcOEt:80/20 as eluent) to afford 260 mg of4-(pyridin-2-yl)but-3-ynyl 2-chlorobenzoate (Yield: 43%) as a yellowoil.

Rf (Cyclohexane/AcOEt:80/20)=0.30

LCMS (RT): 4.19 min; MS (ES+) gave m/z: 286

¹H-NMR (CDCl₃), δ (ppm): 8.55 (s, 1H), 8.06 (s, 1H), 7.98-7.95 (d, 1H),7.67-7.61 (t, 1H), 7.56-7.52 (d, 1H), 7.42-7.37 (m, 2H), 7.24-7.18 (m,1H), 4.55-4.52 (t, 2H), 2.95-2.93 (t, 2H)

Example 236 4-(Pyridin-2-yl)but-3-ynyl 3-chlorobenzoate

According to the protocol described in Example 235(B), the conversion of3-chlorobenzoic acid (330 mg, 2.10 mmol) afforded 350 mg of4-(pyridin-2-yl)but-3-ynyl 3-chlorobenzoate (Yield: 58%) as yellow-oil.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn,

Cyclohexane/AcOEt:80/20 as eluent)

Rf (Cyclohexane/AcOEt:80/20)=0.30

LCMS (RT): 4.53 min; MS (ES+) gave m/z: 286

¹H-NMR (CDCl₃), δ (ppm): 8.58-8.55 (d, 1H), 7.91-7.87 (d, 1H), 7.66-7.60(t, 1H), 7.48-7.38 (m, 3H), 7.35-7.30 (t, 1H), 7.24-7.19 (m, 1H),4.57-4.54 (t, 2H), 2.96-2.93 (t, 2H).

Example 237 3-Chlorophenyl 5-(pyridin-2-yl)pent-4-ynoate 237(A)3-Chlorophenyl pent-4-ynoate

According to the protocol described in Example 235(B), the reactionbetween pent-4-ynoic acid (590 mg, 6.0 mmol) and 3-chlorophenol (771 mg,6.0 mmol) afforded 1.19 g of 3-chlorophenyl pent-4-ynoate (Yield: 95%)as colorless-oil. Purification over silicagel chromatography (prepacked25 g silicagel column, Cyclohexane/AcOEt:90/10 as eluent)

Rf (Cyclohexane/AcOEt:90/10)=0.30

LCMS (RT): 4.68 min; MS (ES+) no MH+ detected

237(B) 3-Chlorophenyl 5-(pyridin-2-yl)pent-4-ynoate

In a dry microwave tube were placed in suspension CuI (26.7 mg, 0.14mmol) and triethylamine (5.30 mL, 37.80 mmol). Then under nitrogenatmosphere, were added the 2-iodopyridine (574 mg, 2.80 mmol),PdCl₂(PPh₃)₂ (98 mg, 0.14 mmol), and triphenyl phosphine polymerbound(190 mg, 0.56 mmol). The suspension was stirred at room temperature forfew minutes, finally the 3-chlorophenyl pent-4-ynoate (580 mg, 2.80mmol) in 0.2 mL of DMF was added, and the reaction mixture is stirred atroom temperature for 30 min. The reaction mixture was stirred and heatedunder micro wave irradiation for 8 min at 120° C. After filtering toremove triphenyl phosphine polymerbound, the triethylamine wasconcentrated under reduce pressure, the residue was dissolved in DCM.The organic layer was washed with saturated NaHCO₃, H₂O and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, Cyclohexane/AcOEt:80/20 as eluent) to afford 210 mg of3-chlorophenyl 5-(pyridin-2-yl)pent-4-ynoate (Yield: 26%) as a yellowoil.

Rf (Cyclohexane/AcOEt:80/20)=0.30

LCMS (RT): 4.33 min; MS (ES+) gave m/z: 286

¹H-NMR (CDCl₃), δ (ppm): 8.59-8.56 (d, 1H), 7.66-7.61 (t, 1H), 7.42-7.38(d, 1H), 7.34-7.17 (m, 4H), 7.06-7.02 (d, 1H), 2.95-2.86 (m, 4H)

Example 238 3-Chlorophenyl 5-(3-fluoropyridin-2-yl)pent-4-ynoate

According to the protocol described in Example 237(B), the reactionbetween 3-chlorophenyl pent-4-ynoate (580 mg, 2.80 mmol) and2-chloro-3-fluoropyridine (370 mg, 2.80 mmol) afforded 111 mg of3-chlorophenyl 5-(3-fluoropyridin-2-yl)pent-4-ynoate (Yield: 13%) asyellow-oil.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, Cyclohexane/AcOEt:80/20 as eluent)

Rf (Cyclohexane/AcOEt:80/20)=0.32

LCMS (RT): 4.61 min; MS (ES+) gave m/z: 304

¹H-NMR (CDCl₃), δ (ppm): 8.42-8.38 (m, 1H), 7.45-7.40 (t, 1H), 7.34-7.17(m, 4H), 7.07-7.03 (m, 1H), 2.95 (s, 4H)

Example 239 2-Chlorophenyl 5-(pyridin-2-yl)pent-4-ynoate 239(A)2-Chlorophenyl pent-4-ynoate

According to the protocol described in Example 235(B), the reactionbetween pent-4-ynoic acid (590 mg, 6.0 mmol) and 2-chlorophenol (771 mg,6.0 mmol) afforded 1.09 g of 2-chlorophenyl pent-4-ynoate (Yield: 87%)as colorless-oil.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, Cyclohexane/AcOEt:90/10 as eluent)

Rf (Cyclohexane/AcOEt:90/10)=0.30

LCMS (RT): 4.41 min; MS (ES+) no MH+ detected

239(B) 2-Chlorophenyl 5-(pyridin-2-yl)pent-4-ynoate

According to the protocol described in Example 237(B), the reactionbetween 2-chlorophenyl pent-4-ynoate (420 mg, 2.00 mmol) and2-iodopyridine (410 mg, 2.00 mmol) afforded 208 mg of 2-chlorophenyl5-(3-fluoropyridin-2-yl)pent-4-ynoate (Yield: 36%) as yellow-oil.Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, Cyclohexane/AcOEt: form 90/10 to 80/20 as eluent)

Rf (Cyclohexane/AcOEt:80/20)=0.32

LCMS (RT): 4.21 min; MS (ES+) gave m/z: 286

¹H-NMR (CDCl₃), δ (ppm): 8.59-8.55 (d, 1H), 7.66-7.61 (t, 1H), 7.47-7.43(d, 1H), 7.42-7.38 (d, 1H), 7.32-7.26 (m, 1H), 7.24-7.16 (m, 3H),3.03-2.98 (m, 2H), 2.96-2.90 (m, 2H)

Example 240 2-Chlorophenyl 5-(2-methylthiazol-4-yl)pent-4-ynoate 240(A)4-Bromo-2-methylthiazole

To a solution of 2,4-Dibromothiazole (1.00 g, 4.10 mmol) in anhydrousEt₂O (14 mL) was added dropwise at −78° C., 2.1 mL of nBuLi 2.5M inhexane (5.30 mmol). The mixture was stirred for 2 h at −78° C. Then asolution of methyl trifluoromethanesulfonate (673 mg, 4.10 mmol) in THF(2 mL) was added dropwise at −78° C., the resulting mixture was stirred30 min at −78° C. The reaction mixture was warmed slowly to roomtemperature. The reaction was cooled with an ice bath at −10° C. andquenched with water. The two layers were separated; the aqueous layerwas extracted with Ethylic ether. The combined organic layers were driedover Na₂SO₄, filtered and concentrated under medium pressure 700 mbar,bath 35° C., because the bromothiazole is very volatile. The product waspurified by flash chromatogtraphy silice 40-60, pack 70 g, Pentane/Et₂O:95/5 as eluent to afford 420 mg of 4-bromo-2-methylthiazole (Yield: 57%)as a colorless oil.

Rf (Pentane/Et₂O: 95/5)=0.32

LCMS (RT): 3.29 min; MS (ES+) gave m/z: 179

240(B) 4-Iodo-2-methylthiazole

To a solution of 4-bromo-2-methylthiazole (418 mg, 2.35 mmol) inanhydrous Et₂O (3 mL) was added dropwise at −78° C., 0.14 mL of nBuLi2.5M in hexane (2.80 mmol). The mixture was stirred for 1 h at −78° C.Then a solution of diiodoethane (1.30 g, 4.70 mmol) in 0.4 mL of Et₂Owas added dropwise at −78° C., and the resulting mixture was stirred 30min at −78° C. The reaction was then warmed slowly to room temperatureover a period of 2 h. The reaction was cooled with a ice bath at −10° C.was quenched with water. The two layers were separated and the aqueouslayer was extracted with Et₂O. The combined organic layers were driedover Na₂SO₄, filtered and concentrated under medium pressure.

Purification over silicagel chromatography (prepacked 10 g silicagelcolumn, Pentane/Et₂O: 95/5 as eluent) to afford 240 mg of4-iodo-2-methylthiazole (Yield: 45%) as a colorless oil.

LCMS (RT): 3.49 min; MS (ES+) gave m/z: 225

240(C) 2-Chlorophenyl 5-(2-methylthiazol-4-yl)pent-4-ynoate

According to the protocol described in Example 237(B), the reactionbetween 2-chlorophenyl pent-4-ynoate (compound 160(A), 290 mg, 1.40mmol) and 4-iodo-2-methylthiazole (315 mg, 1.40 mmol) afforded 145 mg of2-chlorophenyl 5-(2-methylthiazol-4-yl)pent-4-ynoate (Yield: 34%) asyellow-oil.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, Cyclohexane/AcOEt: form 90/10 to 80/20 as eluent)

Rf (Cyclohexane/AcOEt:80/20)=0.32

LCMS (RT): 4.61 min; MS (ES+) gave m/z: 306

¹H-NMR (CDCl₃), δ (ppm): 7.47-7.43 (m, 1H), 7.32-7.26 (m, 1H), 7.23-7.15(m, 3H), 3.00-2.95 (m, 2H), 2.92-2.87 (m, 2H)

Example 2412-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)benzo[d]thiazole

The title compound was prepared in accordance with the general method ofExample 190(F), from 2-bromo-6-(fluoromethyl)pyridine (266 mg, 1.40mmol) and 2-(but-3-ynyl)benzo[d]thiazole (compound 35(A), 260 mg, 1.40mmol). The crude residue was purified over silicagel chromatography(prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 100/0 to 80/20as eluent) to afford 160 mg of2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzo[d]thiazole (Yield:38%) as a beige powder (Mp=74-76° C.).

LCMS (RT): 4.38 min; MS (ES+) gave m/z: 297

Rf (Cyclohexane/AcOEt:80/20)=0.30

¹H-NMR (CDCl₃), δ (ppm): 8.03-7.99 (d, 1H), 7.89-7.85 (d, 1H), 7.73-7.67(t, 1H), 7.51-7.45 (t, 1H), 7.42-7.32 (m, 3H), 5.52-5.43 (d, 2H),3.49-3.44 (t, 2H), 3.09-3.04 (t, 2H)

Example 242 2-(5-(Pyridin-2-yl)pent-4-ynyl)isoindoline-1,3-dione 242(A)5-(Pyridin-2-yl)pent-4-yn-1-ol

In a dry microwave tube were placed in suspension, CuI (57 mg, 0.30mmol) and triethylamine (10.10 ml, 72 mmol). Then under nitrogen, wereadded the 2-bromopyridine (948 mg, 6.0 mmol), PdCl₂(PPh₃)₂ (211 mg, 0.30mmol) and triphenyl phosphine polymerbound (310 mg, 1.20 mmol). Thesuspension was stirred at room temperature for 5 minutes, finallypent-4-yn-1-01 (500 mg, 6.0 mmol) in DMF (8.60 mL) was added, and thereaction mixture was stirred at room temperature for 30 min.

The reaction mixture was stirred and heated with micro wave for 20 minat 120° C. Triethylamine was concentrated under reduce pressure; theresidue was dissolved in DCM. The organic layer was washed with NaHCO₃,H₂O and saturated brine. The organic layer was dried over Na₂SO₄,filtered and concentrated.

Purification by flash chromatography pack 50 g, silice 40-60, DCM/AcOEt:from 100/0 to 50/50 as eluent to afford 702 mg of5-(pyridin-2-yl)pent-4-yn-1-ol (Yield: 72%) as a colorless oil.

LCMS (RT): 1.94 min; MS (ES+) gave m/z: 162

Rf (DCM/AcOEt:50/50)=0.30

242(B) 2-(5-Bromopent-1-ynyl)pyridine

Bromine (3.45 g, 21.4 mmol) was added to a solution oftriphenylphosphine (8.30 g, 30.7 mmol) in DCM (40 mL) cooled to −5° C.The flask was protected from the light and a white precipitate wasformed after 5 min. A solution of the 5-(pyridin-2-yl)pent-4-yn-1-ol (3g, 18.6 mmol) in DCM (10 mL) was added at a rate to raise the reactiontemperature to 5° C. at the end of the addition. The reaction solutionwas cooled to −10° C. and stirred for 5 h. The colour turned dark green.LCMS shown that the reaction was not completed. As no precipitateappeared, ¾ of the solvent were removed under low pressure and themixture cooled down to −10° C., as no precipitate appeared the mixturewas concentrated to remove ¾ of the solvent and then cooled downovernight in the fridge. No precipitate appeared; the reaction was thentaken in saturated NaHCO₃ and extracted with DCM. The organic layer waswashed with brine, dried over MgSO₄, filtrated and concentrated.

The crude was purified by flash pack chromatography in DCM/MeOH 99.5:0.5to afford 1.20 g of 2-(5-bromopent-1-ynyl)pyridine comtaminated withtriphenylphosphine. The compound was used in the next step with nofurther purification.

242(C) 2-(5-(Pyridin-2-yl)pent-4-ynyl)isoindoline-1,3-dione

2-(5-bromopent-1-ynyl)pyridine (118 mg, 0.525 mmol),isoindoline-1,3-dione (74 mg, 0.5 mmol) and potassium carbonate (140 mg,1 mmol) were dissolved in acetone (1 mL). The resulting mixture washeated with microwave at 150° C. for 15 min. The reaction was quenchedwith water, then acetone was evaporated under reduced pressure. Theaqueous layer was extracted with DCM, and the organic layer was washedone time with saturated brine, dried over MgSO₄, filtrated andconcentrated.

Purification by flash chromatography pack 15 g silice 40-60,Cyclohexane/AcOEt:50/50 to afford 30 mg of2-(5-(pyridin-2-yl)pent-4-ynyl)isoindoline-1,3-dione (Yield: 20%) as abeige powder (Mp=127-129° C.).

LCMS (RT): 3.46 min; MS (ES+) gave m/z: 291

Rf (Cyclohexane/AcOEt:50/50)=0.35

¹H-NMR (CDCl₃), δ (ppm): 8.54-8.49 (d, 1H), 7.86-7.83 (m, 2H), 7.72-7.67(m, 2H), 7.62-7.56 (t, 1H), 7.33-7.29 (d, 1H), 7.19-7.14 (m, 1H),3.90-3.84 (t, 2H), 2.57-2.52 (t, 2H), 2.10-2.02 (m, 2H)

Example 243 2-(6-(Pyridin-2-yl)hex-5-ynyl)phthalazin-1(2H)-one 243(A)6-(Pyridin-2-yl)hex-5-yn-1-ol

In a dry microwave tube were placed in suspension CuI (76 mg, 0.4 mmol)and triethylamine (14.60 mL, 104 mmol). Then under nitrogen atmosphere,were added the 2-bromopyridine (1.26 g, 8.00 mmol), PdCl₂(PPh₃)₂ (281mg, 0.40 mmol) and triphenyl phosphine polymerbound (530 mg, 1.60 mmol).The suspension was stirred at room temperature for 5 minutes, finallythe hex-5-yn-1-ol (790 mg, 8.0 mmol) in 11.5 mL of DMF was added, andthe reaction mixture is stirred at room temperature for 30 min.

The reaction mixture was stirred and heated under micro wave irradiationfor 20 min at 120° C. After filtering to remove triphenyl phosphinepolymerbound, the triethylamine was concentrated under reduced pressureand the residue was dissolved in DCM. The organic layer was washed withsaturated NaHCO₃, H₂O and saturated brine. The organic layer was driedover Na₂SO₄, filtered and concentrated.

Purification over silicagel chromatography (prepacked 50 g silicagelcolumn, DCM/AcOEt: from 100/0 to 50/50 as eluent) to afford 1.32 g of6-(pyridin-2-yl)hex-5-yn-1-ol (Yield: 94%) as a colorless oil.

Rf (DCM/AcOEt:50/50)=0.30

LCMS (RT): 2.09 min; MS (ES+) gave m/z: 176

243(B) 2-(6-Bromohex-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 242(A), from 6-(pyridin-2-yl)hex-5-yn-1-ol (1.30 g, 7.50 mmol)to afford 138 mg of 2-(6-bromohex-1-ynyl)pyridine (Yield: 8%) as acolorless oil.

The crude residue was purified over silicagel chromatography (prepacked70 g silicagel column, Cyclohexane/AcOEt:50/50 as eluent).

LCMS (RT): 3.94 min; MS (ES+) gave m/z: 239

Rf (Cyclohexane/AcOEt:50/50)=0.40

243(C) 2-(6-(Pyridin-2-yl)hex-5-ynyl)phthalazin-1(2H)-one

The title compound was prepared in accordance with the general method ofExample 242(B), from 2-(6-bromohex-1-ynyl)pyridine (138 mg, 0.578 mmol)and phthalazin-1(2H)-one (80 mg, 0.55 mmol).

The crude residue was purified over silicagel chromatography (prepacked25 g silicagel column, DCM/MeOH: 98/2 as eluent) to afford 35 mg of2-(6-(pyridin-2-yl)hex-5-ynyl)phthalazin-1(2H)-one (Yield: 21%) as ayellow oil.

LCMS (RT): 3.48 min; MS (ES+) gave m/z: 304

Rf (DCM/MeOH:98/2)=0.30

¹H-NMR (CDCl₃), δ (ppm): 8.55-8.52 (d, 1H), 8.47-8.42 (d, 1H), 8.18 (s,1H), 7.84-7.75 (m, 2H), 7.72-7.68 (d, 1H), 7.63-7.58 (t, 1H), 7.39-7.35(d, 1H), 7.20-7.15 (m, 1H), 4.32-4.29 (t, 2H), 2.54-2.51 (t, 2H),2.07-2.04 (m, 2H), 1.75-1.72 (m, 2H)

Example 244 N-(4-Chlorophenyl)-5-(pyridin-2-yl)pent-4-ynamide 244(A)N-(4-Chlorophenyl)pent-4-ynamide

According to the protocol described in Example 12(A), the conversion of4-chlorobenzenamine (650 mg, 5.10 mmol) afforded 820 mg ofN-(4-chlorophenyl)pent-4-ynamide (Yield: 77%) as brownish solid.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, DCM 100% as eluent)

Rf (100% DCM)=0.35

¹NMR (CDCl₃), δ (ppm): 7.60 (s, 1H), 7.40-6.90 (m, 4H), 2.60-2.40 (m,4H), 1.95 (s, 1H)

244(B) tert-Butyl 4-chlorophenyl(pent-4-ynoyl)carbamate

The title compound was prepared in accordance with the general method ofExample 34(B), from N-(4-chlorophenyl)pent-4-ynamide (820 mg, 3.95 mmol)and (BOC)₂O (1.03 g, 4.74 mmol). The crude residue was purified oversilicagel chromatography (prepacked 25 g silicagel column, DCM 100% aseluent) to afford 1.13 g of tert-butyl4-chlorophenyl(pent-4-ynoyl)carbamate as a colorless oil (Yield: 94%).

Rf (100% DCM)=0.63

LCMS (RT): 4.90 min; MS (ES+) gave m/z: MH+-Boc: 208

244(C) tert-Butyl 4-chlorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate

To a solution of CuI (7.7 mg, 0.041 mmol) in triethylamine (2.28 mL)were added 2-bromopyridine (129 mg, 0.82 mmol) and (PPh₃)₂PdCl₂ (28.7mg, 0.041 mmol). The reaction mixture was cooled to 0° C. and tert-butyl4-chlorophenyl(pent-4-ynoyl)carbamate (250 mg, 0.82 mmol) was added. Thereaction mixture was allowed to warm to room temperature and then heatedunder reflux for 3 h. at 70° C. Triethylamine was evaporated, water wasadded and the aqueous phase was extracted twice with DCM. The organicphase was dried over Na₂SO₄, filtered and concentrated. The cruderesidue was purified by flash chromatography (prepacked 25 g silicagelcolumn, Cyclohexane/AcOEt:70/30 as eluent) to afford 172 mg (Yield: 55%)of tert-butyl 4-chlorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate as ayellow oil.

Rf (Cyclohexane/AcOEt:70/30)=0.18

LCMS (RT): 4.83 min; MS (ES+) gave m/z: 385

244(D) N-(4-Chlorophenyl)-5-(pyridin-2-yl)pent-4-ynamide

According to the protocol described in Example 34(D), the conversion oftert-butyl 4-chlorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate (172mg, 0.45 mmol) afford 67 mg ofN-(4-chlorophenyl)-5-(pyridin-2-yl)pent-4-ynamide (Yield: 53%) as whitepowder (Mp=110-111° C.).

The crude product was triturated twice with a mixture conatiningpentane/isopropyl ether 50/50, to obtain the desired compound as a whitepowder.

LCMS (RT): 3.63 min; MS (ES+) gave m/z: 285

¹NMR (CDCl₃), δ (ppm): 8.55 (s, 1H), 7.70-7.50 (m, 3H), 7.40-7.20 (t,2H), 7.18-7.05 (m, 2H), 7.00-6.90 (m, 1H), 2.85-2.75 (t, 2H), 2.68-2.58(t, 2H)

Example 245 N-(3-Chlorophenyl)-5-(pyridin-2-yl)pent-4-ynamide 245(A)N-(3-Chlorophenyl)pent-4-ynamide

According to the protocol described in Example 12(A), the conversion of3-chlorobenzenamine (650 mg, 5.10 mmol) afforded 630 mg ofN-(3-chlorophenyl)pent-4-ynamide (Yield: 59%) as brownish solid.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, DCM 100% as eluent)

Rf (100% DCM)=0.26

245(B) tert-Butyl 3-chlorophenyl(pent-4-ynoyl)carbamate

The title compound was prepared in accordance with the general method ofExample 34(B), from N-(3-chlorophenyl)pent-4-ynamide (630 mg, 3.03 mmol)and (BOC)₂O (795 mg, 3.64 mmol). The crude residue was purified oversilicagel chromatography (prepacked 25 g silicagel column 100% DCM aseluent) to afford 824 mg of tert-butyl3-chlorophenyl(pent-4-ynoyl)carbamate as a colorless oil (Yield: 88%).

LCMS (RT): 4.93 min; MS (ES+) gave m/z: MH+-Boc: 208

Rf (100% DCM)=0.57

245(C) tert-Butyl 3-chlorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate

The title compound was prepared in accordance with the general method ofExample 244(C), from tert-butyl 3-chlorophenyl(pent-4-ynoyl)carbamate(250 mg, 0.82 mmol) and 2-bromopyridine (129 mg, 0.82 mmol). The cruderesidue was purified over silicagel chromatography (prepacked 25 gsilicagel column cyclohexane/AcOEt:70/30 as eluent) to afford 226 mg oftert-butyl 3-chlorophenyl(pent-4-ynoyl)carbamate as a brown oil (Yield:72%).

LCMS (RT): 4.87 min; MS (ES+) gave m/z: 385

Rf (Cyclohexane/AcOet:70/30)=0.18

245(D) N-(3-Chlorophenyl)-5-(pyridin-2-yl)pent-4-ynamide

According to the protocol described in Example 34(D), the conversion oftert-butyl 3-chlorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate (226mg, 0.58 mmol) afford 140 mg ofN-(3-chlorophenyl)-5-(pyridin-2-yl)pent-4-ynamide (Yield: 84%) as beigepowder (Mp=167.8-168.8° C.).

The crude product was triturated twice with a mixture containingpentane/isopropyl ether 50/50, to obtain the desired compound as a beigepowder.

LCMS (RT): 3.58 min; MS (ES+) gave m/z: 285

¹NMR (CDCl₃), δ (ppm): 8.50 (d, 1H), 7.70-7.10 (m, 8H), 2.85-2.72 (t,2H), 2.65-2.55 (t, 2H)

Example 246 N-(2,4-Difluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide 246(A)N-(2,4-Difluorophenyl)pent-4-ynamide

According to the protocol described in Example 12(A), the conversion of2,4-difluorobenzenamine (658 mg, 5.10 mmol) afforded 630 mg ofN-(2,4-difluorophenyl)pent-4-ynamide (Yield: 59%) as brownish solid.

Purification over silicagel chromatography (prepacked 25 g silicagelcolumn, DCM 100% as eluent)

Rf (100% DCM)=0.35

¹NMR (CDCl₃), δ (ppm): 8.30-8.10 (m, 1H), 7.40 (s, 1H), 6.90-6.70 (m,2H), 2.50 (s, 4H), 1.98 (s, 1H).

246(B) tert-Butyl 2,4-difluorophenyl(pent-4-ynoyl)carbamate

The title compound was prepared in accordance with the general method ofExample 34(B), from N-(2,4-difluorophenyl)pent-4-ynamide (630 mg, 3.01mmol) and (BOC)₂O (789 mg, 3.61 mmol). The crude residue was purifiedover silicagel chromatography (prepacked 25 g silicagel column, 100% DCMas eluent) to afford 924 mg of tert-butyl2,4-difluorophenyl(pent-4-ynoyl)carbamate as a colorless oil (Yield:99%).

LCMS (RT): 4.82 min; MS (ES+) gave m/z: MH⁺-Boc: 210)

Rf (100% DCM)=0.63

246(C) tert-Butyl2,4-difluorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate

The title compound was prepared in accordance with the general method ofExample 244(C), from tert-butyl2,4-difluorophenyl(pent-4-ynoyl)carbamate_(250 mg, 0.82 mmol) and2-bromopyridine (129 mg, 0.82 mmol). The crude residue was purified oversilicagel chromatography (prepacked 25 g silicagel columncyclohexane/AcOEt:70/30 as eluent) to afford 193 mg of tert-butyl2,4-difluorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate as a brown oil(Yield: 61%).

LCMS (RT): 4.72 min; MS (ES+) gave m/z: 387

Rf (Cyclohexane/AcOet:70/30)=0.18

246(D) N-(2,4-Difluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide

According to the protocol described in Example 34(D), the conversion oftert-butyl 2,4-difluorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate(193 mg, 0.50 mmol) afford 123 mg ofN-(2,4-difluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide (yield: 86%) abeige powder (Mp=132-133.2° C.).

The crude product was triturated twice with a mixture conatiningpentane/isopropyl ether 50/50, to obtain the desired compound as a beigepowder.

LCMS (RT): 3.20 min; MS (ES+) gave m/z: 287.

¹NMR (CDCl₃), δ (ppm): 8.50 (d, 1H), 8.30-8.10 (m. 1H), 7.70-7.10 (m,4H), 6.90-6.70 (m, 2H), 2.90-2.80 (t, 2H), 2.70-2.60 (t, 2H).

Example 2472-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide

The title compound was prepared in accordance with the general method ofExample 184, from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine (39mg, 0.22 mmol, Example 189(D)) and 2-chlorobenzoyl chloride (50 mg, 0.28mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 7:3) to yield 13.5 mg (43 μmol, 19%) of2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide as acolorless oil.

LCMS (RT): 3.52 min; MS (ES+) gave m/z: 317.1, 319.1.

Example 2482-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzenesulfonamide

The title compound was prepared in accordance with the general method ofExample 184, from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine (39mg, 0.22 mmol, Example 189(D)) and 2-chlorobenzenesulfonyl chloride (60mg, 0.28 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 7:3) to yield 14.4 mg (41 μmol, 19%) of2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzenesulfonamideas an orange oil.

LCMS (RT): 3.92 min; MS (ES+) gave m/z: 353.1, 355.1.

Example 2492-(4-(4-(4-Fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-(but-3-ynyl)-4-(4-fluorophenyl)-2H-1,2,3-triazole (150mg, 0.70 mmol, Example 254(B)) and 2-bromopyridine (122 mg, 0.77 mmol).The crude residue was purified by flash chromatography (DCM/MeOH 99:1)to yield 84 mg (0.29 mmol, 41%) of2-(4-(4-(4-fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as ayellow solid (M.P.=83.5-84.5° C.).

LCMS (RT): 4.07 min; MS (ES+) gave m/z: 293.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.16 (t, J=7.2, 2H), 4.71 (t, J=7.2, 2H),7.08-7.16 (2H), 7.21 (ddd, J=1.2, 4.8 and 7.8, 1H), 7.35 (d, J=7.8, 1H),7.58-7.65 (m, 1H), 7.73-7.78 (2H), 7.81 (s, 1H), 8.55 (d, J=4.5, 1H).

Example 2502-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-(but-3-ynyl)-4-(4-fluorophenyl)-2H-1,2,3-triazole (150mg, 0.70 mmol, Example 254(B)) and 2-bromo-6-(fluoromethyl)pyridine (146mg, 0.77 mmol, Example 190(E)). The crude residue was purified by flashchromatography (DCM/MeOH 99.5:0.5 to 99:1) to yield 101 mg (0.31 mmol,45%) of2-(fluoromethyl)-6-(4-(4-(4-fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridineas a yellow solid (M.P.=84-86° C.).

LCMS (RT): 4.44 min; MS (ES+) gave m/z: 325.2.

Rf (DCM/MeOH 98:2)=0.3.

¹H-NMR (CDCl₃), δ (ppm): 3.16 (t, J=7.5, 2H), 4.71 (t, J=7.5, 2H),5.36-5.54 (m, 2H), 7.08-7.16 (2H), 7.31 (d, J=7.8, 1H), 7.40 (d, J=7.8,1H), 7.66-7.72 (m, 1H), 7.73-7.79 (2H), 7.81 (s, 1H).

Example 251 2-Chloro-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide251(A) 2-(4-(Pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione

The title compound was prepared in accordance with the general method ofExample 1, from 2-iodopyridine (453 mg, 2.21 mmol) and2-(but-3-ynyl)isoindoline-1,3-dione (400 mg, 2.01 mmol, Example 189(B)).The crude residue was purified by flash chromatography(cyclohexane/AcOEt 70:30) to yield 250 mg (0.90 mmol, 45%) of2-(4-(pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as.

LCMS (RT): 3.43 min; MS (ES+) gave m/z: 277.1.

251(B) 4-(Pyridin-2-yl)but-3-yn-1-amine

The title compound was prepared in accordance with the general method ofExample 189(D), from 2-(4-(pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione(250 mg, 0.90 mmol) to yield 32 mg (0.22 mmol, 24%) of4-(pyridin-2-yl)but-3-yn-1-amine as a white solid.

251(C) 2-Chloro-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide

The title compound was prepared in accordance with the general method ofExample 184, from 4-(pyridin-2-yl)but-3-yn-1-amine (16 mg, 0.11 mmol)and 2-chlorobenzene-1-sulfonyl chloride (30 mg, 0.14 mmol). The cruderesidue was purified by flash chromatography (cyclohexane/AcOEt 7:3) toyield 11.2 mg (35 mmol, 32%) of2-chloro-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide as a brownoil.

LCMS (RT): 3.48 min; MS (ES+) gave m/z: 321.1, 323.1.

Example 2525-(6-(Fluoromethyl)pyridin-2-yl)-N-(4-fluoro-2-methyl-phenyl)pent-4-ynamide252(A)[5-(6-Fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-2-methyl-phenyl)-carbamicacid tert-butyl ester

The title compound was prepared in accordance with the general method ofExample 1, from 2-bromo-6-(fluoromethyl)pyridine (150 mg, 0.79 mmol,Example 190(E)) and (4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamicacid tert-butyl ester (241 mg, 0.79 mmol, 188(B)). Reaction time: 3hours. The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 260 mg (0.63 mmol, 79%) of[5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-2-methyl-phenyl)-carbamicacid tert-butyl ester as a white solid.

Rf (cyclohexane/AcOEt 4:1)=0.2.

252(B)5-(6-(Fluoromethyl)pyridin-2-yl)-N-(4-fluoro-2-methyl-phenyl)pent-4-ynamide

The title compound was prepared in accordance with the general method ofExample 34(D), from[5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-2-methyl-phenyl)-carbamicacid tert-butyl ester (260 mg, 0.63 mmol). After the work-up, the cruderesidue was washed with diisopropyl ether to yield 190 mg (0.60 mmol,97%) of5-(6-(fluoromethyl)pyridin-2-yl)-N-(4-fluoro-2-methyl-phenyl)pent-4-ynamideas a white powder (M.P.=122-125° C.).

LCMS (RT): 3.08 min; MS (ES+) gave m/z: 315.1.

¹NMR(CDCl₃), δ (ppm): 2.23 (s, 3H), 2.72 (t, J=7.5, 2H), 2.90 (t, J=7.5,2H), 5.36-5.54 (m, 2H), 6.84-6.94 (2H), 7.32 (d, J=7.5, 1H), 7.40 (d,J=7.5, 1H), 7.60-7.79 (2H).

Example 2535-(4-Fluoro-phenyl)-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one253(A) 5-Bromo-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one

The title compound was prepared in accordance with the general method ofExample 109(D), from 4-(pyridin-2-yl)but-3-yn-1-ol (700 mg, 4.76 mmol,Example 3(A)) and 5-bromo-1H-pyridin-2-one (870 mg, 5.00 mmol). Thecrude residue was purified by flash chromatography (cyclohexane/AcOEt9:1) to yield 334 mg (1.10 mmol, 23%) of5-bromo-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one.

253(B)5-(4-Fluoro-phenyl)-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one

The title compound was prepared in accordance with the general method ofExample 83, from 5-bromo-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one(50 mg, 0.16 mmol) and 4-fluorophenylboronic acid (35 mg, 0.25 mmol).The crude residue was purified by flash chromatography(cyclohexane/AcOEt 9:1) to yield 18 mg (57 μmol, 34%) of5-(4-fluoro-phenyl)-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one.

LCMS (RT): 4.66 min; MS (ES+) gave m/z: 319.2.

Example 2542-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine254(A) 4-(4-Fluorophenyl)-2H-1,2,3-triazole

The title compound was prepared in accordance with the general method ofExample 179(A), from (E)-1-fluoro-4-(2-nitrovinyl)benzene (2.00 g, 12.0mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 1.08 g (6.62 mmol, 55%) of4-(4-fluorophenyl)-2H-1,2,3-triazole as an orange solid.

Rf (cyclohexane/AcOEt 4:1)=0.1.

254(B) 1-(But-3-ynyl)-4-(4-fluorophenyl)-1H-1,2,3-triazole and2-(but-3-ynyl)-4-(4-fluorophenyl)-2H-1,2,3-triazole

The title compounds were prepared in accordance with the general methodof Example 109(D), from 4-(4-fluorophenyl)-2H-1,2,3-triazole (1.08 g,6.62 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 95:5 to 80:20) to yield 200 mg (0.92 mmol, 14%) of1-(but-3-ynyl)-4-(4-fluorophenyl)-1H-1,2,3-triazole as a yellow solidand 300 mg (1.40 mmol, 21%) of2-(but-3-ynyl)-4-(4-fluorophenyl)-2H-1,2,3-triazole as a orange solid.

1-(But-3-ynyl)-4-(4-fluorophenyl)-1H-1,2,3-triazole

LCMS (RT): 3.57 min; MS (ES+) gave m/z: 216.1.

Rf (cyclohexane/AcOEt 4:1)=0.1.

2-(But-3-ynyl)-4-(4-fluorophenyl)-2H-1,2,3-triazole

LCMS (RT): 4.20 min; MS (ES+) gave m/z: 216.1.

Rf (cyclohexane/AcOEt 4:1)=0.5.

254(C)2-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 1-(but-3-ynyl)-4-(4-fluorophenyl)-1H-1,2,3-triazole (100mg, 0.47 mmol) and 2-bromo-6-(fluoromethyl)pyridine (97 mg, 0.51 mmol,Example 190(E)). Reaction time: 2 hours. The crude residue was purifiedby flash chromatography (DCM/MeOH 98.5:1.5) to yield 32 mg (0.10 mmol,21%) of2-(fluoromethyl)-6-(4-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridineas a yellow solid (M.P.=100-103° C.).

LCMS (RT): 3.90 min; MS (ES+) gave m/z: 325.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.10 (t, J=6.6, 2H), 4.67 (t, J=6.6, 2H),5.37-5.55 (m, 2H), 7.08-7.15 (2H), 7.30 (d, J=8.1, 1H), 7.42 (d, J=8.1,1H), 7.67-7.74 (m, 1H), 7.77-7.83 (2H), 7.93 (s, 1H).

Example 2558-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 255(A)8-Chloro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 223(D), from 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (4.96 g,20.1 mmol, Example 223(C)) and 3-chloropyridin-2-amine (1.29 g, 10.0mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 2.00 g (7.22 mmol, 72%) of8-chloro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine as abrown solid.

¹H-NMR (CDCl₃), δ (ppm): 0.14 (s, 12H), 2.66 (t, J=6.9, 2H), 3.06 (t,J=7.2, 2H), 6.69 (t, J=7.2, 1H), 7.21 (d, J=7.5, 1H), 7.53 (s, 1H), 7.99(d, J=6.6, 1H).

255(B) 2-(But-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 108(B), from8-chloro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (2.00g, 7.22 mmol). The crude residue was taken in Et₂O, filtered andconcentrated to yield 1.09 mg (5.31 mmol, 74%) of2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine as a yellow solid.

¹H-NMR (CDCl₃), δ (ppm): 1.97 (t, J=2.7, 1H), 2.66 (t, J=7.2, 2H), 3.07(t, J=6.9, 2H), 6.69 (t, J=6.9, 1H), 7.21 (d, J=7.2, 1H), 7.54 (s, 1H),8.0 (d, J=6.9, 1H).

255(C) 8-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine (500 mg,2.44 mmol) and 2-bromopyridine (405 mg, 2.57 mmol). The crude residuewas purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield293 mg (1.04 mmol, 43%) of8-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine as awhite solid (M.P.=106-107° C.).

LCMS (RT): 2.22 min; MS (ES+) gave m/z: 282.1, 284.0.

Rf (DCM/MeOH 98:2)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 2.92 (t, J=7.2, 2H), 3.18 (t, J=7.2, 2H),6.65-6.71 (m, 1H), 7.15-7.24 (2H), 7.35 (d, J=7.8, 1H), 7.57-7.63 (2H),8.01 (d, J=7.2, 1H), 8.52-8.56 (m, 1H).

Example 2568-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine (500 mg,2.44 mmol, Example 255(B)) and 2-bromo-6-(fluoromethyl)pyridine (487 mg,2.57 mmol, Example 190(E)). The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 420 mg (1.34 mmol, 55%) of8-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridineas a slightly yellow solid (M.P.=73-74.5° C.).

LCMS (RT): 2.57 min; MS (ES+) gave m/z: 314.1, 316.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 2.92 (t, J=7.2, 2H), 3.18 (t, J=7.2, 2H),5.36-5.55 (m, 2H), 6.66-6.73 (m, 1H), 7.22 (dd, J=0.9 and 7.8, 1H), 7.32(d, J=8.1, 1H), 7.37 (d, J=7.8, 1H), 7.57 (s, 1H), 7.65-7.72 (m, 1H),8.00 (dd, J=0.9 and 6.6, 1H).

Example 2572-(4-(4-(4-Fluorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine257(A) 4-(4-Fluorophenyl)-5-methyl-2H-1,2,3-triazole

The title compound was prepared in accordance with the general method ofExample 179(A), from (E)-1-fluoro-4-(2-nitroprop-1-enyl)benzene (1.01 g,5.60 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 407 mg (2.30 mmol, 41%) of4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazole as a slightly yellowsolid.

Rf (cyclohexane/AcOEt 4:1)=0.05.

257(B) 2-(But-3-ynyl)-4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazole and1-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl12H-1,2,3-triazole

The title compounds were prepared in accordance with the general methodof Example 109(D), from 4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazole(407 mg, 2.30 mmol). The crude residue was purified by flashchromatography (cyclohexane/AcOEt 95:5 to 80:20) to yield 265 mg (1.16mmol, 51%) of2-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazole as acolorless oil and 87 mg (0.38 mmol, 17%) of1-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole as a whitesolid.

2-(But-3-ynyl)-4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazole

LCMS (RT): 4.32 min; MS (ES+) gave m/z: 230.1.

Rf (cyclohexane/AcOEt 4:1)=0.4.

1-(But-3-ynyl)-4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole

LCMS (RT): 3.63 min; MS (ES+) gave m/z: 230.1.

Rf (cyclohexane/AcOEt 4:1)=0.1.

257(C)2-(4-(4-(4-Fluorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from2-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazole (265 mg,1.16 mmol) and 2-bromopyridine (201 mg, 1.27 mmol). Reaction time: 2hours. The crude residue was purified by flash chromatography (DCM/MeOH99:1) to yield 306 mg (1.00 mmol, 86%) of24444-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridineas a brown oil.

LCMS (RT): 4.19 min; MS (ES+) gave m/z: 307.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 2.46 (s, 3H), 3.12 (t, J=7.2, 2H), 4.63 (t,J=7.2, 2H), 7.08-7.16 (2H), 7.18-7.23 (m, 1H), 7.36 (dd, J=0.9 and 7.5,1H), 7.58-7.67 (3H), 8.52-8.56 (m, 1H).

Example 2582-(4-(4-(4-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from1-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole (87 mg,0.38 mmol, Example 257(B)) and 2-bromopyridine (66 mg, 0.42 mmol).Reaction time: 2 hours. The crude residue was purified by flashchromatography (DCM/MeOH 99:1) to yield 68 mg (0.22 mmol, 58%) of2-(4-(4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridineas a white powder (M.P.=130-131° C.).

LCMS (RT): 3.56 min; MS (ES+) gave m/z: 307.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 2.53 (s, 3H), 3.11 (t, J=7.2, 2H), 4.57 (t,J=7.2, 2H), 7.09-7.17 (2H), 7.20-7.25 (m, 1H), 7.34 (d, J=7.8, 1H),7.59-7.70 (3H), 8.55 (d, J=4.5, 1H).

Example 2592-(4-(4-(2-Chlorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine259(A) 4-(2-Chlorophenyl)-2H-1,2,3-triazole

The title compound was prepared in accordance with the general method ofExample 179(A), from (E)-1-chloro-2-(2-nitrovinyl)benzene (2.06 g, 11.2mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 4:1) to yield 1.05 g (5.85 mmol, 52%) of4-(2-chlorophenyl)-2H-1,2,3-triazole as an orange solid.

Rf (cyclohexane/AcOEt 4:1)=0.1.

259(B) 2-(But-3-ynyl)-4-(2-chlorophenyl)-2H-1,2,3-triazole and1-(but-3-ynyl)-4-(2-chlorophenyl)-1H-1,2,3-triazole

The title compounds were prepared in accordance with the general methodof Example 109(D), from 4-(2-chlorophenyl)-2H-1,2,3-triazole (1.05 g,5.85 mmol). The crude residue was purified by flash chromatography(cyclohexane/AcOEt 95:5 to 80:20) to yield 660 mg (2.85 mmol, 50%) of2-(but-3-ynyl)-4-(2-chlorophenyl)-2H-1,2,3-triazole as a yellow oil and400 mg (1.73 mmol, 30%) of1-(but-3-ynyl)-4-(2-chlorophenyl)-1H-1,2,3-triazole as a yellow oil.

2-(But-3-ynyl)-4-(2-chlorophenyl)-2H-1,2,3-triazole

LCMS (RT): 4.47 min; MS (ES+) gave m/z: 232.1.

Rf (cyclohexane/AcOEt 4:1)=0.4.

1-(But-3-ynyl)-4-(2-chlorophenyl)-1H-1,2,3-triazole

LCMS (RT): 3.86 min; MS (ES+) gave m/z: 232.1.

Rf (cyclohexane/AcOEt 4:1)=0.2.

259(C)2-(4-(4-(2-Chlorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-(but-3-ynyl)-4-(2-chlorophenyl)-2H-1,2,3-triazole (200mg, 0.86 mmol) and 2-bromopyridine (150 mg, 0.95 mmol). The cruderesidue was purified by flash chromatography (DCM/MeOH 98.5:1.5) toyield 120 mg (0.39 mmol, 45%) of2-(4-(4-(2-chlorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as abrown oil.

LCMS (RT): 4.34 min; MS (ES+) gave m/z: 309.1, 311.1.

Rf (DCM/MeOH 98:2)=0.3.

¹H-NMR (CDCl₃), δ (ppm): 3.18 (t, J=7.5, 2H), 4.75 (t, J=7.5, 2H), 7.21(ddd, J=1.2, 4.8 and 7.5, 1H), 7.28-7.39 (3H), 7.45-7.48 (m, 1H),7.58-7.65 (m, 1H), 7.85-7.88 (m, 1H), 8.14 (s, 1H), 8.55 (d, J=4.8, 1H).

Example 2602-(4-(4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 1-(but-3-ynyl)-4-(2-chlorophenyl)-1H-1,2,3-triazole (200mg, 0.86 mmol, Example 259(B)) and 2-bromopyridine (150 mg, 0.95 mmol).The crude residue was purified by flash chromatography (DCM/MeOH 99:1)to yield 93.4 mg (0.30 mmol, 35%) of2-(4-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as ayellow oil.

LCMS (RT): 3.74 min; MS (ES+) gave m/z: 309.1, 311.1.

Rf (DCM/MeOH 98:2)=0.2.

¹H-NMR (CDCl₃), δ (ppm): 3.12 (t, J=6.6, 2H), 4.70 (t, J=6.6, 2H),7.20-7.25 (m, 1H), 7.26-7.29 (m, 1H), 7.34-7.44 (3H), 7.59-7.66 (m, 1H),8.24 (dd, J=1.8 and 7.5, 1H), 8.40 (s, 1H), 8.56 (d, J=4.8, 1H).

Example 2616,8-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine261(A)6,8-Difluoro-2-(4-(trimethylsilyl)but-3-ynyl)H-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 223(D), from 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (2.0 g,8.1 mmol, Example 223(C)) and 3,5-difluoropyridin-2-amine (0.56 g, 4.30mmol). The crude residue was purified by flash chromatography (DCM 100%to DCM/MeOH 99:1) to yield 200 mg (2.02 mmol, 18%) of6,8-difluoro-2-(4-(trimethylsilyl)but-3-ynyl)H-imidazo[1,2-a]pyridine asa brown solid.

261(B) 2-(But-3-ynyl)-6,8-difluoroH-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 108(B), from6,8-difluoro-2-(4-(trimethylsilyl)but-3-ynyl)H-imidazo[1,2-a]pyridine(200 mg, 2.02 mmol). The crude residue was taken in ether, filtered andconcentrated to yield 150 mg (0.73 mmol, 100%) of2-(but-3-ynyl)-6,8-difluoroH-imidazo[1,2-a]pyridine as a brown solid.

261(C)6,8-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine

The title compound was prepared in accordance with the general method ofExample 1, from 2-(but-3-ynyl)-6,8-difluoroH-imidazo[1,2-a]pyridine (150mg, 0.73 mmol) and 2-bromo-6-(fluoromethyl)pyridine (200 mg, 1.05 mmol,Example 190(E)). The crude residue was purified by flash chromatography(DCM/MeOH 99:1 to 98:2) to yield 110 mg (0.35 mmol, 48%) of6,8-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridineas a yellow solid (M.P.=113-114° C.).

LCMS (Tr): 3.28 min; MS (ES+) gave m/z: 316.2.

Rf (DCM/MeOH 98:2)=0.1.

¹H-NMR (CDCl₃), δ (ppm): 2.92 (t, J=7.2, 2H), 3.14 (t, J=7.8, 2H), 5.46(d, J=46.8, 2H), 6.83-6.89 (m, 1H), 7.31 (d, J=7.8, 1H), 7.38 (d, J=7.5,1H), 7.58 (d, J=3.0, 1H), 7.70 (t, J=7.5, 1H), 7.89 (m, 1H).

Formulation Examples

Typical examples of recipes for the formulation of the invention are asfollows:

1) Tablets

Compound of the example 256 5 to 50 mg Di-calcium phosphate 20 mgLactose 30 mg Talcum 10 mg Magnesium stearate 5 mg Potato starch ad 200mg

In this example, the compound of the example 256 can be replaced by thesame amount of any of the described examples 1 to 261.

2) Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the described example, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

3) Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol andwater.

4) Ointment

Compound of the example 256 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5g White petroleum 15 g Water ad 100 g

In this example, the compound 256 can be replaced by the same amount ofany of the described examples 1 to 261.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

1.-43. (canceled) 44.6-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine, or apharmaceutically acceptable salt thereof.